U.S. patent number 7,834,010 [Application Number 10/583,829] was granted by the patent office on 2010-11-16 for modulators of peripheral 5-ht receptors.
This patent grant is currently assigned to Serodus AS. Invention is credited to Bjarne Brudeli, Jo Klaveness, Finn Olav Levy.
United States Patent |
7,834,010 |
Klaveness , et al. |
November 16, 2010 |
**Please see images for:
( Certificate of Correction ) ** |
Modulators of peripheral 5-HT receptors
Abstract
The invention relates to modulators of peripheral 5-HT
receptors, particularly 5-HT4 receptors, said modulators
essentially selective for peripheral 5-HT receptors over receptors
of the central nervous system. The invention allows for the
treatment, amongst others, of gastrointestinal disorders, lower
urinary tract disorders, and cardiovascular disorders without side
effects related to CNS activity.
Inventors: |
Klaveness; Jo (Oslo,
NO), Levy; Finn Olav (Oslo, NO), Brudeli;
Bjarne (Oslo, NO) |
Assignee: |
Serodus AS (Oslo,
NO)
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Family
ID: |
34707211 |
Appl.
No.: |
10/583,829 |
Filed: |
December 23, 2004 |
PCT
Filed: |
December 23, 2004 |
PCT No.: |
PCT/NO2004/000399 |
371(c)(1),(2),(4) Date: |
April 05, 2007 |
PCT
Pub. No.: |
WO2005/061483 |
PCT
Pub. Date: |
July 07, 2005 |
Prior Publication Data
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Document
Identifier |
Publication Date |
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US 20070254874 A1 |
Nov 1, 2007 |
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Foreign Application Priority Data
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Dec 23, 2003 [DK] |
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2003 01924 |
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Current U.S.
Class: |
514/230.2;
544/89 |
Current CPC
Class: |
A61P
1/04 (20180101); C07D 211/58 (20130101); A61P
1/00 (20180101); A61P 1/18 (20180101); C07D
405/12 (20130101); A61K 31/415 (20130101); C07D
401/12 (20130101); A61P 13/00 (20180101); A61P
31/18 (20180101); A61P 9/04 (20180101); A61K
31/428 (20130101); A61K 31/404 (20130101); A61P
9/00 (20180101); A61K 31/4184 (20130101); A61P
1/08 (20180101); A61P 7/02 (20180101); C07D
209/14 (20130101); C07D 211/26 (20130101); A61P
13/02 (20180101); A61K 31/445 (20130101); A61P
35/00 (20180101); C07D 211/22 (20130101); A61K
31/343 (20130101); A61P 9/06 (20180101); A61P
1/06 (20180101) |
Current International
Class: |
A61K
31/536 (20060101); C07D 265/12 (20060101) |
Field of
Search: |
;514/230.2 ;544/89 |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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1 149 832 |
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Oct 2001 |
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EP |
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11-292846 |
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Oct 1999 |
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JP |
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WO 93/18036 |
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Sep 1993 |
|
WO |
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WO 96/10027 |
|
Apr 1996 |
|
WO |
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WO 01/93849 |
|
Dec 2001 |
|
WO |
|
Other References
International Search Report for International Application No.
PCT/NO2004/000399 dated Aug. 17, 2005. cited by other .
Muller-Lissner, et al. "Tegaserod, a 5-HT.sub.4 receptor partial
agonist, relieves symptoms in irritable bowel syndrome patients
with abdominal pain, bloating and constipation." Aliment Pharmacol
Ther. 15:1655-1666 (2001). cited by other .
Mutschler, et al. "Arzneimittelwirkungen." WYG, Stuttgart. 462-466
(2001). cited by other .
Sanger, et al. "SB-207266: 5-HT.sub.4 receptor antagonism in human
isolated gut and prevention of 5-HT-evoked sensitization of
peristalsis and increased defaecation in animal models."
Neurogastroenterol. Mot. 10:271-279 (1998). cited by other .
Awapara, Jorge. "2-Aminoethanesulfinic Acid: An Intermediate in the
Oxidation of Cysteine in vivo." Journal of Biological Chemistry.
183-188 (1952). cited by other .
Weller et al. "The Detection of 3-Indoleacetic Acid in Cauliflower
Heads. Chromatographic Behavior of Some Indole Compounds." 76:
629-630 (1954). cited by other .
Karl-Heinz et al. "The Serotonin 5-Ht.sub.4 Receptor. 2.
Structure-Activity Studies of the Indole Carbazimidamide Class of
Agonists." J. Med. Chem. 38:2331-2338 (1995). cited by other .
Kato, Hideo et al. "Preparation of benzamidopiperidinocarboxylates
and pharmaceuticals for treatment of digestive system disease."
Abstract. Jan. 31, 2001. cited by other.
|
Primary Examiner: Solola; Taofiq A
Attorney, Agent or Firm: Knobbe Martens Olson & Bear
LLP
Claims
The invention claimed is:
1. A compound represented by formula IV-P ##STR00086## wherein L is
absent or selected from the group consisting of straight chain or
branched optionally substituted C.sub.1-10-alkyl, optionally
substituted C.sub.2-10-alkenyl, optionally substituted
C.sub.2-10-alkynyl, C.sub.1-10-alkylamine, C.sub.1-10-alkoxy,
C.sub.2-10-alkenyloxy, C.sub.2-10-alkynyloxy,
C.sub.1-10-alkoxycarbonyl, C.sub.2-10-alkenyloxycarbonyl,
C.sub.2-10-alkynyloxycarbonyl; and A is selected from the group
consisting of --C(O)--OR.sup.1, --OP(O)OR.sup.2OR.sup.2,
--P(O)OR.sup.2OR.sup.2, --SOhd 2OR.sup.2, and PO.sub.3H; wherein
R.sup.1 and R.sup.2 are independently selected from the group
consisting of H, a counter-ion M, C.sub.1-15-alkyl,
C.sub.3-8-cycloalkyl, aryl, and R.sup.1,2 wherein R.sup.1,2 is
R'--O--C(O)--R'', R'--C(O)--O--R'', R'--C(O)--O--R'', wherein R'
and R'' are independently selected from the group consisting of
C.sub.1-15-alkyl, C.sub.3-8-cycloalkyl and aryl; R.sup.13 is
selected from the group consisting of H, halogen, NH.sub.2, and
C.sub.1-6-alkyl; and R.sup.16 is selected from the group consisting
of H, halogen, OH, O--C.sub.1-6-alkyl, and C.sub.1-6-alkyl.
2. A method of treating a cardiovascular disorder in an individual
in need thereof, comprising administering a therapeutically
effective amount of the compound of claim 1, or a pharmaceutically
acceptable salt thereof, to said individual.
3. A method of treating a gastrointestinal disorder in an
individual in need thereof, comprising administering a
therapeutically effective amount of the compound of claim 1, or a
pharmaceutically acceptable salt thereof, to said individual.
4. The method of claim 2, wherein the cardiovascular disorder is
selected from the group consisting of tachycardia, bradycardia,
cardioexcitation, cardiodepression, arrhythmia, fibrillation,
atrial fibrillation, Paroxysmal Supraventricular Tachycardia
(PSVT), thromoembolisms and VTE.
5. The method of claim 3, wherein the gastrointestinal disorder is
selected from the group consisting of irritable bowel syndrome,
gastrointestinal hypomotility disordersugastro-esophageal reflux,
heartburn, mild oesophagitis, functional or nonulcer dyspensia,
gastroparesis, nausea, vomiting, early satiety in the elderly,
paraneoplastic of HIV-associated gastroparesis, drug-induced delays
in gastric emptying, functional bowel obstructions, bowel
obstructions caused by pancreatic cancer or drugs, and emesis.
6. A method of treating a lower urinary tract disorder in an
individual in need thereof comprising administering the compound of
claim 1, or a pharmaceutically acceptable salt thereof, to said
individual.
7. A pharmaceutical composition, comprising: a compound according
to claim 1; and a pharmaceutically acceptable excipient.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a U.S. National Phase Application under 35
U.S.C. .sctn.371 of International Patent Application No.:
PCT/NO2004/000399, filed Dec. 23, 2004 designating the United
States of America, and published in English on Jul. 7, 2005, which
claims priority to Denmark Patent Application No.: PA 2003 01924,
filed Dec. 23, 2003, all of which are hereby expressly incorporated
by reference in their entireties.
FIELD OF THE INVENTION
The invention relates to modulators of peripheral 5-HT receptors,
particularly 5-HT4, receptors said modulators essentially selective
for peripheral 5-HT receptors over receptors of the central nervous
system. The invention allows for the treatment, amongst others, of
gastrointestinal disorders, lower urinary tract disorders, and
cardiovascular disorders without side effects related to CNS
activity.
BACKGROUND OF THE INVENTION
5-Hydroxytryptamine (5-HT) is an important signalling molecule in
the human body, and has important effects both as a
neurotransmitter and as a locally acting signalling molecule with
e.g. vasoactive effects. During the past 20 years 14 different 5-HT
receptors have been identified and classified into 7 different
subgroups (5-HT.sub.1, 5-HT.sub.2, 5-HT.sub.3, 5-HT.sub.4,
5-HT.sub.5, 5-HT.sub.6 and 5-HT.sub.7), based on structural and
pharmacological criteria as well as signal transduction properties.
Additional diversity arises from e.g. alternative splicing of e.g.
5-HT.sub.4 (e.g. 5-HT.sub.4(a), 5-HT.sub.4(b) etc.) and 5-HT.sub.7
receptors, and of RNA editing of e.g. 5-HT.sub.2C receptors.
5-HT.sub.4 is found to play a central role in diseases in organs
like the heart, the gastrointestinal system, the urinary bladder
and central nervous system (CNS).
5-HT.sub.4 receptor modulators, agonists and antagonists alike, are
found to be useful for the treatment of a variety of diseases such
as gastroesophageal reflux disease, gastrointestinal disease,
gastric motility disorder, non-ulcer dyspepsia, functional
dyspepsia, irritable bowel syndrome, constipation, dyspepsia,
oesophagitis, gastroesophageal disease, nausea, central nervous
system disease, Alzheimer's disease, cognitive disorder, emesis,
migraine, neurological disease, pain, and cardiovascular disorders
such as cardiac failure and heart arrhythmia. Further
gastrointestinal disorders suitable for prophylaxis or treatment of
the symptoms of Irritable Bowel Syndrome, including abdominal pain
and disrupted colonic motility.
Since 5-HT.sub.4 receptors are located both inside and outside the
CNS, 5-HT.sub.4 receptor agonists and antagonists will have effects
both inside and outside the CNS, unless their design prevents their
access to or causes them to preferentially localise to only one of
these compartments. When addressing 5-HT.sub.4 receptors located
outside the CNS, effects on receptors inside the CNS may represent
undesirable side-effects of the treatment, and vice versa. The
present invention seeks to avoid this problem by presenting
5-HT.sub.4 receptor agonists and antagonists which will not
penetrate the blood-brain barrier and thus will not have access to
5-HT.sub.4 receptors located inside the CNS.
Moreover, the problem of poor targeting of 5-HT receptor ligands is
aggravated by the fact that the receptor activity is diminished
upon frequent binding. Unwanted or unselective binding is undesired
in this context also.
Several modulators with affinity for 5-HT.sub.4 receptors are known
in the state of the art. This includes agonists, antagonists and
partial agonists. Modulators of 5-HT.sub.4 receptors are today in
active development as potential therapeutic drugs.
U.S. Pat. No. 6,552,046 discloses the modification of the
piperidinyl nitrogen of cisapride with a moiety wherein an acidic
group may be in close proximity to the basic nitrogen. Moreover,
despite recognising that cisapride has CNS side effects, it
modifies cisapride with an ester moiety for purposes of avoiding
cytochrome P-450 due to degradation of the ester by esterases. Most
remarkably, U.S. Pat. No. 6,552,046 observes that cisapride enters
the central nervous system and binds to 5-HT4 receptors, indicating
that cisapride may have centrally-mediated effects. It further
states compounds of U.S. Pat. No. 6,552,046 can be used in the
treatment of: 1) cognitive disorders, including but not limited to
Alzheimer's disease; 2) behavioural disorders, including but not
limited to schizophrenia, mania, obsessive- compulsive disorder,
and psychoactive substance use disorders; 3) mood disorders,
including but not limited to depression and anxiety; and 4)
disorders of control of autonomic function, including but not
limited to essential hypertension and sleep disorders.
U.S. Pat. No. 6,624,163 (Pfizer) discloses imidazopyridines as
5-HT.sub.4 modulators. Notably, none of the embodiments of the
invention comprise an acidic moiety. This recent attempt in the
area of 5-HT modulators is silent to means of differentiation
between 5-HT related CNS disorders to gastrointestinal or cardiac
disorders. The novel compounds are directed to everything from
neurological diseases to heartburn. Each of the embodiments of U.S.
Pat. No. 6,624,163 are suitable substrates for modification with an
acidic moiety according to the present invention.
U.S. Pat. No. 6,632,827 seeks to minimise side effects with the use
of an optically pure form of norcisapride in the treatment of
gastrointestinal disorders yet concerns itself with the associated
serious CNS side effects such as memory loss, sleep disorders,
depression, and psychoactive distress. Each of the embodiments of
U.S. Pat. No. 6,632,827 are suitable substrates for modification
with an acidic moiety according to the present invention US
2001/0031751 provides novel 5-HT4 antagonists, but does not seek to
differentiate the CNS-from the peripherally-located receptors and
thus intends their use in both CNS and gastrointestinal or
cardiovascular disorders. Notably, none of the embodiments of the
invention comprise an acidic moiety. Each of the embodiments of US
2001/0031751 are suitable substrates for modification with an
acidic moiety according to the present invention.
SUMMARY OF THE INVENTION
A principal object of the invention is providing 5-HT.sub.4
receptor modulators selective to peripheral receptors, essentially
to the exclusion of delivery to CNS located receptors. The
invention accomplishes this by modifying existing modulators and
allows for the design and preparation of new modulators which
comprise an acidic moiety so that the modulator is unable to cross
the blood-brain barrier.
An essential feature of 5-HT modulators, particularly 5-HT4
modulators, is the presence of a basic nitrogen (termed BN in
formulas of the invention). The present inventors have found that
the presence of an acidic moiety, particularly one wherein the
acidic hydrogen of the acidic moiety is at least 2 atoms from the
basic nitrogen, dramatically improves the selectivity of these
modulators for peripheral 5-HT receptors compared to those of the
central nervous system. The present inventors have modified
existing 5-HT modulators and prepared entirely novel 5-HT
modulators which, due to comprising both an acidic moiety and a
basic nitrogen, will provide for improved treatment of conditions
affected by modulating of peripheral 5-HT receptors and with
reduced side effects, due to the selectivity over receptors of the
central nervous system.
A general aspect of the invention relates to the treatment of a
disease associated, at least in part, with peripheral 5-HT receptor
comprising administering a compound of the invention, preferably
with a peripheral 5-HT4 receptor, preferably essentially whilst not
modulating a 5-HT receptor of the central nervous system.
The invention relates to a compound which fulfils the following: i)
a binding affinity to a 5-HT receptor with a pK.sub.i of at least
5; ii) comprises at least one basic nitrogen atom; iii) comprises
at least one acidic moiety with a pKa of no more than 6.4, or a
salt or ester thereof.
A further aspect of the invention relates to a compound having a
binding pK.sub.i for a 5-HT receptor of at least 5 and is of the
formula I BN-L-A I wherein BN is a basic nitrogen moiety; and -A is
an acidic moiety with a pKa of no more than 6.4 or an ester
thereof;
wherein BN-L-A comprises at least 3 consecutive chemical bonds
between BN and the acidic moiety.
An important aspect of the invention relates to compound of formula
II, Ar--C(O)-E-G-BN-L-A II wherein Ar is selected from the group
consisting of an optionally substituted aryl ring, an optionally
substituted aryl ring fused with one or more non-aromatic
optionally substituted carbocylic rings, an optionally substituted
aryl ring fused with one or more optionally substituted
non-aromatic heterocyclic rings, an optionally substituted aryl
ring fused with one or more optionally substituted aromatic or
heteroaromatic rings, C(O) is absent or a carbonyl carbon; E is
absent or selected from the group consisting of O and NH; G is
absent or selected from the group consisting of C.sub.1-6-alkyl,
C.sub.3-7-cycloalkyl, C.sub.1-6-alkyl-C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-6-alkyl;
wherein BN is a basic nitrogen moiety selected from the group
consisting of an amine group, an amide group, a carbamate or a
carbamate derivative, urea or a urea derivative, a carbazimidamide,
a nitrogen-containing heterocyclic, a nitrogen-containing
heteroarylic ring, and an azabicyclic ring; L is absent or selected
from the group consisting of a straight chain or branched
optionally substituted C.sub.1-10-alkyl, optionally substituted
C.sub.2-10-alkenyl, optionally substituted C.sub.2-10-alkynyl,
C.sub.1-10-alkylamine, C.sub.1-10-alkoxy, C.sub.2-10-alkenyloxy,
C.sub.2-10-alkynyloxy, C.sub.1-10-alkoxycarbonyl,
C.sub.2-10-alkenyloxycarbonyl, C.sub.2-10-alkynyloxycarbonyl or
combinations thereof; and A is selected from the group consisting
of C(O)--OR.sup.1, OP(O)OR.sup.2OR.sup.2, P(O)OR.sup.2OR.sup.2,
SO.sub.2OR.sup.2, SO.sub.3H, OSO.sub.3H, and PO.sub.3H; wherein
R.sup.1 and R.sup.2 are independently selected from the group
consisting of H, M, C.sub.1-15-alkyl, C.sub.3-8-cycloalkyl, aryl,
and R.sup.1,2 wherein R.sup.1,2 is R'--O--C(O)--R'',
R'--O--C(O)--O--R'', R'--C(O)--O--R'', wherein R' and R'' are
independently selected from the group consisting of
C.sub.1-15-alkyl, C.sub.3-8-cycloalkyl and aryl.
An interesting embodiment of the compounds of the invention is a
compound according of the formula IV-P
##STR00001## wherein L is absent or selected from the group
consisting of straight chain or branched optionally substituted
C.sub.1-10-alkyl, optionally substituted C.sub.2-10-alkenyl,
optionally substituted C.sub.2-10-alkynyl, C.sub.1-10-alkylamine,
C.sub.1-10-alkoxy, C.sub.2-10-alkenyloxy, C.sub.2-10-alkynyloxy,
C.sub.1-10-alkoxycarbonyl, C.sub.2-10-alkenyloxycarbonyl,
C.sub.2-10-alkynyloxycarbonyl; and A is selected from the group
consisting of --C(O)--OR.sup.1, --OP(O)OR.sup.2OR.sup.2,
--P(O)OR.sup.2OR.sup.2, --SO.sub.2OR.sup.2, and PO.sub.3H; wherein
R.sup.1 and R.sup.2 are independently selected from the group
consisting of H, M, C.sub.1-15-alkyl, C.sub.3-8-cycloalkyl, aryl,
and R.sup.1,2 wherein R.sup.1,2 is R'--O--C(O)--R'',
R'--O--C(O)--O--R'', R'--C(O)--O--R'', wherein R' and R'' are
independently selected from the group consisting of
C.sub.1-15-alkyl, C.sub.3-8-cycloalkyl and aryl; R.sup.13 is
selected from the group consisting of H, halogen, NH.sub.2, and
C.sub.1-6-alkyl; and R.sup.16 is selected from the group consisting
of H, halogen, OH, O--C.sub.1-6-alkyl, and C.sub.1-6-alkyl.
A particularly interesting embodiment of compounds of the formula
II are compounds of formula VI,
##STR00002## wherein X and Y are independently selected from the
group consisting of NH, O, C, and S; L is absent or selected from
the group consisting of straight chain or branched optionally
substituted C.sub.1-10-alkyl, optionally substituted
C.sub.2-10-alkenyl, optionally substituted C.sub.2-10-alkynyl,
C.sub.1-10-alkylamine, C.sub.1-10-alkoxy, C.sub.2-10-alkenyloxy,
C.sub.2-10-alkynyloxy, C.sub.1-10-alkoxycarbonyl,
C.sub.2-10-alkenyloxycarbonyl, C.sub.2-10-alkynyloxycarbonyl; A is
selected from the group consisting of --C(O)--OR.sup.1,
--OP(O)OR.sup.2OR.sup.2, --P(O)OR.sup.2OR.sup.2,
--SO.sub.2OR.sup.2, and PO.sub.3H; wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting of H, M,
C.sub.1-15-alkyl, C.sub.3-8-cycloalkyl, aryl, and R.sup.1,2 wherein
R.sup.1,2 is R'--O--C(O)--R'', R'--O--C(O)--O--R'',
R'--C(O)--O--R'', wherein R' and R'' are independently selected
from the group consisting of C.sub.1-15-alkyl, C.sub.3-8-cycloalkyl
and aryl; and R.sup.16 and R.sup.13 are independently selected from
the group consisting of H, OH, halogen, NH.sub.2,
O--C.sub.1-6-alkyl, and C.sub.1-6-alkyl.
A further aspect of the invention relates to a method of treating a
cardiovascular disorder comprising administering a compound of the
invention. Suitably, the cardiovascular disorder is selected from
tachycardia, bradycardia, cardioexcitation, cardiodepression,
arrhythmia, fibrillation, atrial fibrillation, Paroxysmal
Supraventricular Tachycardia (PSVT), thromoembolisms and VTE.
A particularly interesting aspect of the invention relates to a
method of treating gastrointestinal disorders, such as irritable
bowel syndrome, comprising administering a compound of the
invention. Alternatively stated, an aspect of the invention relates
to the use of the compounds of the invention for the preparation of
a medicament for the prophylaxis or treatment of gastrointestinal
disorders suitable and for symptoms of Irritable Bowel Syndrome,
including abdominal pain and disrupted colonic motility; diarrhea;
constipation; urinary incontinence and anal incontinence
The treatment of lower urinary tract disorders, such as e.g.
hyperactive bladder, comprising administering a compound of the
invention is a further aspect of the invention.
The treatment of primary or secondary hyperaldosteronism comprising
administering a compound of the invention is a further aspect of
the invention.
A suitable class of modulators of 5-HT receptors which are subject
to the improvements provided by the present invention have a
aromatic moiety (Ar), an amide or ester (C(O)--O or C(O)--NH), an
optional spacer moiety (G), and the aforementioned basic nitrogen
(BN). Accordingly, a suitable object of the invention is the use of
compounds of the formula II for the treatment of conditions
affected by the modulation of 5-HT receptors, particularly 5-HT4
receptors, wherein Ar--C(O)-E-G-BN are as defined above, and L is a
linker moiety comprising at least 2 atoms and L is an acidic moiety
such as a carboxylic acid, a sulphonic acid, a sulphoric acid, a
phosphonic acid, and a phosphoric acid, or esters of the acidic
moiety.
DESCRIPTION OF THE INVENTION
The invention relates to a compound which fulfils the following: i)
a binding affinity to a 5-HT receptor with a pK.sub.i of at least
5; ii) comprises at least one basic nitrogen atom; iii) comprises
at least one acidic moiety with a pKa of no more than 6.4, or a
salt or ester thereof. Without being bound to a particular theory,
it is anticipated that the acidic moiety is to be spaced from the
acidic nitrogen atom such that the acidic moiety does not interfere
with the binding capacity of the nitrogen atom believed to
constitute part of the pharmacophore in 5-HT modulators.
The acidic moiety (A) is thus suitably spaced from the basic
nitrogen (BN) by at least 2 atoms. Correspondingly, L in compounds
of the invention preferably comprises at least 2 atoms.
In a typical embodiment of the present invention, the compounds of
the invention further comprise iv) an aromatic or heteroaromatic
ring, more typically an aromatic ring. The acidic moiety may be
covalently linked to the aromatic or heteroaromatic ring. Without
being bound to a particular theory, it is believed that the acidic
moiety is to be within a 20 atom space from either the basic
nitrogen or the aromatic/heteroaromatic ring. Typically, the basic
nitrogen or the aromatic/heteroaromatic ring is less than 16 atoms,
such as less than 10, from the acidic moiety.
An acidic moiety is a group that is at least 90% ionic form at
physiological pH, more typically at least 95%, even more typically
at least 99% of the group is in ionic form. In a preferred
embodiment, the acidic moiety has a pKa of no more than 6, more
preferably, no more than 5.5, such as no more than 5.4, 5.3, 5.3,
5.2, 5.1, 5.0. In a most preferred form, the compounds of the
invention have a pKa of less than 5.0, such as less than 4.5.
The acidic moiety may be in the form of its ester, in its free ion
form, or in a salt form. In the embodiment wherein the acidic
moiety is in the form of its ester, after hydrolysis of the ester
to the acid or to its free ion form is at least 90% ionic form at
physiological pH, more typically at least 95%, even more typically
at least 99% of the group is in ionic form. It is to be understood
that esters of the acidic moiety are characterised in that their
hydrolysis consequently result in the presence of the acid in its
protonated form or in its free ion form.
Suitable salts include but are not limited to the counter-ion M
selected from the group comprising sodium, potassium, calcium,
magnesium, aluminium, iron, and zinc ions. The inventor
contemplates salts with ammonia and organic nitrogenous bases
strong enough to form salts with carboxylic acids. Bases useful for
the formation of pharmaceutically acceptable nontoxic base addition
salts of the compound of the present invention form a class whose
limits are readily understood by those skilled in the art.
In the present context, the term "halogen" includes fluorine,
chlorine, bromine and iodine. In the present context the term
"aryl" is intended to mean a carbocyclic aromatic ring or ring
system. Moreover, the term "aryl" includes fused ring systems
wherein at least two aryl rings, or at least one aryl and at least
one C.sub.3-8-cycloalkyl share at least one chemical bond.
Illustrative examples of "aryl" rings include optionally
substituted phenyl, naphthalenyl, phenanthrenyl, anthracenyl,
tetralinyl, fluorenyl, indenyl, and indanyl. A preferred aryl group
is phenyl. The term "aryl" relates to aromatic, preferably
benzenoid groups connected via one of the ring-forming carbon
atoms, and optionally carrying one or more substituents selected
from halo, hydroxy, amino, cyano, nitro, alkylamido, acyl,
C.sub.1-6 alkoxy, C.sub.1-6 alkyl, C.sub.1-6 hydroxyalkyl,
C.sub.1-6 aminoalkyl, C.sub.1-6 alkylamino, alkylsulfenyl,
alkylsulfinyl, alkylsulfonyl, sulfamoyl, or trifluoromethyl. As
stated, preferred aryl groups are phenyl, and, most suitably,
substituted phenyl groups, carrying one or two, same or different,
of the substituents listed above.
The term "heterocyclic ring" is intended to mean three-, four-,
five-, six-, seven-, and eight-membered rings wherein carbon atoms
together with from 1 to 3 heteroatoms constitute said ring. A
heterocyclyl may optionally contain one or more unsaturated bonds
situated in such a way, however, that an aromatic .pi.-electron
system does not arise. The heteroatoms are independently selected
from oxygen, sulphur, and nitrogen.
A heterocyclic ring may further contain one or more carbonyl or
thiocarbonyl functionalities, so as to make the definition include
oxo-systems and thio-systems such as lactams, lactones, cyclic
imides, cyclic thioimides, cyclic carbamates, and the like.
Heterocyclic rings may optionally also be fused to aryl rings, such
that the definition includes bicyclic structures. Preferred such
fused heterocyclyl groups share one bond with an optionally
substituted benzene ring. Examples of benzo-fused heterocyclyl
groups include, but are not limited to, benzimidazolidinone,
tetrahydroquinoline, and methylenedioxybenzene ring structures.
Illustrative examples of "heterocyclic rings" are the heterocycles
tetrahydrothiopyran, 4H-pyran, tetrahydropyran, piperidine,
1,3-dioxin, 1,3-dioxane, 1,4-dioxin, 1,4-dioxane, piperazine,
1,3-oxathiane, 1,4-oxathiin, 1,4-oxathiane,
tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide,
barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin,
dihydrouracil, morpholine, trioxane, hexahydro-1,3,5-triazine,
tetrahydrothiophene, tetrahydrofuran, pyrroline, pyrrolidine,
pyrrolidone, pyrrolidione, pyrazoline, pyrazolidine, imidazoline,
imidazolidine, 1,3-dioxole, 1,3-dioxolane, 1,3-dithiole,
1,3-dithiolane, isoxazoline, isoxazolidine, oxazoline, oxazolidine,
thiazoline, thiazolidine, 1,3-oxathiolane. Binding to the
heterocycle may be at the position of a heteroatom or via a carbon
atom of the heterocycle, or, for benzo-fused derivatives, via a
carbon of the benzenoid ring.
Suitable embodiments of the acidic moiety or an ester thereof
selected from the group consisting of C(O)--OR.sup.1,
OP(O)OR.sup.2OR.sup.2, P(O)OR.sup.2OR.sup.2, SO.sub.2OR.sup.2,
SO.sub.3H, OSO.sub.3H, and PO.sub.3H wherein R.sup.1 and R.sup.2
are independently selected from the group consisting of H, M,
C.sub.1-15-alkyl, C.sub.3-8-cycloalkyl, aryl, and R.sup.1,2 wherein
R.sup.1,2 is R'--O--C(O)--R'', R'--O--C(O)--O--R'',
R'--C(O)--O--R'', wherein R' and R'' are independently selected
from the group consisting of C.sub.1-15-alkyl, C.sub.3-8-cycloalkyl
and aryl. Salts of these acid moieties imply that at least one of
R1 and R.sup.2 is M. M is a counterion as defined above.
A particularly interesting embodiment of the compounds of the
invention are esters of the previously described acidic moiety.
Typical esters include alkyl esters, substituted alkyl esters, aryl
esters, substituted aryl esters and acyloxyalkyl esters. Exemplary
embodiments of esters of acidic moieties include
##STR00003##
In another suitable embodiment, the compound of the invention has a
pK.sub.i of at least 5.5, such as at least 6.
The compounds of the invention may be agonist, antagonists, reverse
agonists, partial agonists, or partial antagonists of a 5-HT
receptor. Typically, the compound of the invention will have either
agonist or partial agonistic activity towards at least one receptor
sub-group and optionally concomitant antagonist or partial
antagonistic activity toward at least one other receptor sub-group.
In a preferred embodiment of the invention, the compounds of the
invention have a binding affinity with a pK.sub.i of at least 5,
such as at least 5.5, preferably at least 6 to the 5-HT4 or 5-HT3
receptor subgroup.
In a typical embodiment, the compound of the invention has a
binding pK.sub.i for a 5-HT receptor of at least 5 and is of the
formula I BN-L-A I wherein BN is a basic nitrogen moiety; and -A is
an acidic moiety with a pKa of no more than 6.4 or an ester
thereof;
wherein BN-L-A comprises at least 3 consecutive chemical bonds
between BN and the acidic moiety.
In a preferred embodiment, L is a linker comprising at least 2
atoms. In the preferred embodiments where the acidic moiety or an
ester thereof is selected from the group consisting of
C(O)--OR.sup.1, OP(O)OR OR.sup.2, P(O)OR OR.sup.2,
SO.sub.2OR.sup.2, SO.sub.3H, OSO.sub.3H, and PO.sub.3H, the 3
consecutive chemical bonds, typically 4 consecutive chemical bonds,
are between the nitrogen atom and C atom of --C(O)--OR.sup.1, the P
atom of --OP(O)OR.sup.2OR.sup.2, the P atom of
--P(O)OR.sup.2OR.sup.2, the P atom of PO.sub.3H and the S atom of
--SO.sub.2OR.sup.2.
The basic nitrogen moiety may be in the any array of organic forms
of nitrogen. Suitable forms of the basic nitrogen moiety may be
selected from the group comprising an amine group, amide group,
carbamates and urea derivatives, carbazimidamides, a
nitrogen-containing heterocyclic or heteroarylic ring, including
azabicycles.
Amine groups can be primary, secondary or tertiary amines. Suitable
nitrogen-containing heterocyclic or heteroaryl include pyridyl
(pyridinyl), pyrimidinyl, thiazolyl, pyrazolyl, imidazolyl,
tetrazolyl, indolyl, indolenyl, quinolinyl, isoquinolinyl,
benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl,
2-pyrrolidonyl, pyrrolinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, decahydroquinolinyl or
octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl,
2H,6H-1,5,2-dithiazinyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl,
imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl,
pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl,
isoindolyl, 3H-indolyl, indolyl, 1H-indazolyl, purinyl,
4H-quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl,
naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl,
4aH-carbazole, carbazole, .beta.-carbolinyl, phenanthridinyl,
acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl,
phenothiazinyl, furazanyl, phenoxazinyl, pyrrolidinyl, pyrrolinyl,
imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,
piperidinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl,
morpholinyl or oxazolidinyl. Preferable heterocyclic groups include
piperidino, morpholino, thiamorpholino, pyrrolidino, pyrazolino,
pyrazolidino, pyrazoryl, piperazinyl, thienyl, oxazolyl,
tetrazolyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolyl,
pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl and quinolyl.
In a typical embodiment of compounds of the formula BN-L-A, the
compounds of the invention have the formula II, Ar--C(O)-E-G-BN-L-A
II wherein Ar is an monocyclic or polycyclic aromatic or
heteroaromatic; C(O) is absent or a carbonyl carbon; and E is
absent or selected from the group consisting of O and NH; G is
selected from the group consisting of C.sub.1-6-alkyl,
C.sub.3-7-cycloalkyl, C.sub.1-6-alkyl-C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-6-alkyl; or wherein G-N together form
a C.sub.3-7-heteroalkyl, or a
C.sub.1-6-alkyl-C.sub.3-7-heteroalkyl.
A highly commercially relevant aspect of the invention is directed
to a compound of formula II, Ar--C(O)-E-G-BN-L-A II wherein Ar is
selected from the group consisting of an optionally substituted
aryl ring, an optionally substituted aryl ring fused with one or
more non-aromatic optionally substituted carbocylic rings, an
optionally substituted aryl ring fused with one or more optionally
substituted non-aromatic heterocyclic rings, an optionally
substituted aryl ring fused with one or more optionally substituted
aromatic or heteroaromatic rings, C(O) is absent or a carbonyl
carbon; E is absent or selected from the group consisting of O and
NH; G is absent or selected from the group consisting of
C.sub.1-6-alkyl, C.sub.3-7-cycloalkyl,
C.sub.1-6-alkyl-C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-6-alkyl;
wherein BN is a basic nitrogen moiety selected from the group
consisting of an amine group, an amide group, a carbamate or a
carbamate derivative, urea or a urea derivative, a carbazimidamide,
a nitrogen-containing heterocyclic, a nitrogen-containing
heteroarylic ring, and an azabicyclic ring; L is absent or selected
from the group consisting of straight chain or branched optionally
substituted C.sub.1-10-alkyl, optionally substituted
C.sub.2-10-alkenyl, optionally substituted C.sub.2-10-alkynyl,
C.sub.1-10-alkylamine, C.sub.1-10-alkoxy, C.sub.2-10-alkenyloxy,
C.sub.2-10-alkynyloxy, C.sub.1-10-alkoxycarbonyl,
C.sub.2-10-alkenyloxycarbonyl, C.sub.2-10-alkynyloxycarbonyl or
combinations thereof; and A is selected from the group consisting
of C(O)--OR.sup.1, OP(O)OR.sup.2OR.sup.2, P(O)OR.sup.2OR.sup.2,
SO.sub.20R.sup.2, SO.sub.3H, OSO.sub.3H, and PO.sub.3H; wherein
R.sup.1 and R.sup.2 are independently selected from the group
consisting of H, M, C.sub.1-15-alkyl, C.sub.3-8-cycloalkyl, aryl,
and R.sup.1,2 wherein R.sup.1,2 is R'--O--C(O)--R'',
R'--O--C(O)--O--R'', R'--C(O)--O--R'', wherein R' and R'' are
independently selected from the group consisting of
C.sub.1-15-alkyl, C.sub.3-8-cycloalkyl and aryl.
Suitably, the basic nitrogen moiety may be selected from the group
consisting of pyridyl (pyridinyl), pyrimidinyl, thiazolyl,
pyrazolyl, imidazolyl, tetrazolyl, indolyl, indolenyl, quinolinyl,
isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl,
pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydroquinolinyl,
tetrahydroisoquinolinyl, decahydroquinolinyl or
octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl,
2H,6H-1,5,2-dithiazinyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl,
imidazolyl, pyrazolyl, isothiazolyl, isoxazolyl, oxazolyl,
pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl,
isoindolyl, 3H-indolyl, indolyl, 1H-indazolyl, purinyl,
4H-quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl,
naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl,
4aH-carbazole, carbazole, .beta.-carbolinyl, phenanthridinyl,
acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl,
phenothiazinyl, furazanyl, phenoxazinyl, pyrrolidinyl, pyrrolinyl,
imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl,
piperidinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl,
morpholinyl or oxazolidinyl. Preferable heterocyclic groups include
piperidino, morpholino, thiamorpholino, pyrrolidino, pyrazolino,
pyrazolidino, pyrazoryl, piperazinyl, thienyl, oxazolyl,
tetrazolyl, thiazolyl, imidazolyl, imidazolinyl, pyrazolyl,
pyridyl, pyrimidinyl, pyrrolyl, pyrrolidinyl and quinolyl, each of
which may be optional substituted.
In a most preferred embodiment of the compounds of the invention,
the basic nitrogen moiety is selected from the group consisting of
carbazimidamide and optional substituted piperidinyl.
In terms of the aryl moiety, Ar may be suitably selected from
optionally substituted benzyl, naphthalene, indoline, indole,
oxazinoindoline, indolizine, isoindoline, indene, indane, indazole,
azulene, benzimidazole, benzofuran, benzothiophene, benzthiazole,
purine, 4H-quinolizine, quinoline, isoquinoline, cinnoline,
phthalazine, quinazoline, quinoxaline, 1,3-naphthyridine,
pteridine, coumaran, benzodioxane, benzopyran, chroman, isochroman,
carbazole, acridine, phenazine, phenothiazine, phenoxazine,
thianthrene, phenanthrene, anthracene, tetraline, fluorene, and
acenaphthylene, each of which may be optionally substituted.
The inventors have demonstrated in the enclosed examples the
general applicability of the term Ar by demonstrating at least the
suitability of embodiments wherein Ar is selected from benzyl,
naphthalene, indole, benzodioxane, indazole, and oxazinoindole.
Typically, in embodiments wherein Ar is a bi- or polycyclic system,
the bond between Ar and the C(O), G or the basic nitrogen moiety
stems from the atom of Ar neighbouring the atoms shared by the
fused bicyclic system.
As can be seen from the Examples, in typical embodiments, L may be
absent or selected from the group consisting of optionally
substituted Cl.sub.1-10-alkyl, C.sub.1-10-alkylamine,
C.sub.1-10-alkoxy, and C.sub.1-10-alkoxycarbonyl. L is typically
selected from straight chain or branched optionally substituted
C.sub.1-10-alkyl, C.sub.1-10-alkylamine or C.sub.1-10-alkoxy. In
embodiments wherein L is a branched chain optionally substituted
C.sub.1-10-alkyl, C.sub.1-10-alkylamine or C.sub.1-10-alkoxy, there
may be one or two acidic moieties A, namely L-A may be of the
formula
##STR00004## where X is selected from the group consisting of C and
N and i, j, and k are independently selected from a whole number
selected from the group consisting of 0-10 (wherein the sum i+j+k
is typically less than 10; and one or both of the A groups is as
defined above, the other being absent. An exemplary embodiment of
branched optionally substituted C.sub.1-10-alkyl,
C.sub.1-10-alkylamine or C.sub.1-10-alkoxy is
The Examples demonstrate the great suitability of embodiments
wherein A is selected from the group consisting of
--C(O)--OR.sup.1, and --P(O)OR.sup.2OR.sup.2, wherein R.sup.1 and
R.sup.2 are independently selected from the group consisting of H,
M, C.sub.1-15-alkyl, C.sub.3-8-cycloalkyl, and aryl. Particularly
interesting are the carboxylic acids or their alkyl esters, such as
their trichloroethyl esters.
##STR00005##
Typically, G is absent or selected from the group consisting of
C.sub.1-6-alkyl, preferably absent or C.sub.1-3-alkyl.
In a combination of preferred embodiments, as can be seen from the
examples, compounds wherein L is absent or selected from the group
consisting of optionally substituted C.sub.1-8-alkyl and wherein A
is selected from the group consisting of --C(O)--OR.sup.1, and
--P(O)OR.sup.2OR.sup.2, wherein R.sup.1 and R.sup.2 are
independently selected from the group consisting of H and
C.sub.1-15-alkyl are highly relevant.
In a further combination of interesting embodiments, G is absent or
C.sub.1-3-alkyl; the basic nitrogen moiety is selected from the
group consisting of carbazimidamide and optional substituted
piperidinyl; and L is absent or selected from the group consisting
of optionally substituted C.sub.1-8-alkyl.
A further aspect of the invention is directed to the use of a
compound of formula II as defined supra, or a composition
comprising said compound or a salt of said compound for the
preparation of a medicament for the treatment of a cardiovascular
disorder. The cardiovascular disorder is typically selected from
the group consisting of tachycardia, bradycardia, cardioexcitation,
cardiodepression, arrhythmia, fibrillation, atrial fibrillation,
Paroxysmal Supraventricular Tachycardia (PSVT), thromoembolisms and
VTE.
A related aspect of the invention is directed to the use of a
compound of formula II as defined herein, or a composition
comprising said compound or a salt of said compound for the
preparation of a medicament for the treatment of a gastrointestinal
disorder or lower urinary tract disorder. The gastrointestinal
disorder may be selected from the group consisting of irritable
bowel syndrome; gastrointestinal hypomotility disorders;
gastro-esophageal reflux, such as heartburn or mild oesophagitis;
functional or nonulcer dyspensia; gastroparesis; nausea and
vomiting; early satiety in the elderly; paraneoplastic of
HIV-associated gastroparesis; drug-induced delays in gastric
emptying and functional bowel obstructions, such as bowel
obstructions caused by pancreatic cancer or drugs; and emesis. An
related aspect of the invention relates to the use of the compounds
of the invention for the preparation of a medicament for the
prophylaxis or treatment of gastrointestinal disorders suitable and
for symptoms of Irritable Bowel Syndrome, including abdominal pain
and disrupted colonic motility; diarrhea; constipation; urinary
incontinence and anal incontinence.
WO 96/10027, in the preparation of compounds for use in the
treatment of conditions involving a decreased motility of the
intestine, prepared the 4-aminobenzofuran carboxylates
##STR00006## which, in a suitable embodiment of the present
invention, are disclaimed only as such and in the context of their
use for the preparation of a medicament for use in the treatment of
conditions involving a decreased motility of the intestine.
In an alternative embodiment of the compounds invention as such and
in the context of their use for the preparation of a medicament for
use in the treatment of conditions involving a decreased motility
of the intestine, Ar--C(O)-E is not a 4-aminobenzofuran, not a
4-aminocoumaran, and not a 4-aminochroman carboxylate The
4-position is to be understood as para to carboxylate.
In a further alternative embodiment of the compounds of the present
invention as such and in the context of their use for the
preparation of a medicament for use in the treatment of conditions
involving a decreased motility of the intestine, Ar is not a
4-aminobenzofuran, not a 4-aminocoumaran, and not a
4-aminochroman--the 4-position being para to the remainder amide or
carboxylate in Ar--C(O)-E-G-BN-L-A. WO 01/93849 in the preparation
of compounds for the treatment of gastroesophageal reflux disease
disclosed benzamide derivatives. In an alternative embodiment of
the compounds invention as such and in the context of compounds for
the treatment of gastroesophageal reflux disease, when Ar is a
phenyl thrice substituted with NH.sub.2, Cl, and/or CH.sub.3, A is
a carboxylic acid or ester, L is not an optionally substituted
C.sub.2-8-alkyl, C.sub.2-8-alkoxy, C.sub.2-8-alkenyloxy,
C.sub.2-8-alkynyloxy, C.sub.2-8-alkoxycarbonyl,
C.sub.2-8-alkenyloxycarbonyl or C.sub.2-8-alkynyloxycarbonyl.
The inventors further disclaim, as such, and in the context of the
context of improving gastrointestinal tract motility, compounds of
the formula
##STR00007## wherein R is selected from H, methyl, ethyl,
isopropyl, sec-butyl, and 4-fluorophenyl and n is 0, 1, 2, 3, or 4.
More typically, the inventors herein disclaim compounds, as such,
wherein n is from 0 to 8 and R is hydrogen, lower alkyl, or
substituted aryl.
Generally stated, the invention relates to method of treating a
disease associated, at least in part, with peripheral 5HT receptor
comprising administering a compound of formula I, II, III, IV, V,
or VI. Accordingly, one aspect of the invention is directed to a
method of treating a cardiovascular disorder comprising
administering a compound of formula I, II, III, IV, V, or VI.
Similarly, a further aspect relates to method of treating
gastrointestinal disorders comprising administering a compound of
the invention. A still further aspect of the invention is directed
a method of treating lower urinary tract disorders comprising
administering a compound of the invention.
Most typically, the compounds of the invention act and are intended
to act on the 5-HT.sub.4 receptor subgroup.
In a typical embodiment of compounds of the formula BN-L-A, the
compounds of the invention have the formula II,
Ar--C(O)-E-G-BN-L-A, wherein Ar is an aromatic or heteroaromatic,
including fused aromatic systems; E is absent or selected from the
group consisting of O and NH; G is selected from the group
consisting of C.sub.1-6-alkyl, C.sub.3-7-cycloalkyl,
C.sub.1-6-alkyl-C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-6-alkyl; or wherein G-BN together form
a C.sub.3-7-heteroalkyl, or a
C.sub.1-6-alkyl-C.sub.3-7-heteroalkyl; and L-A is selected from the
group consisting of C.sub.2-6-alkyl-C(O)--OR.sup.1,
C.sub.2-6-alkyl-OP(O)OR.sup.2OR.sup.2,
C.sub.2-6-alkyl-P(O)OR.sup.2OR.sup.2,
C.sub.2-6-alkyl-SO.sub.2OR.sup.2, C.sub.2-6-alkyl-PO.sub.3H,
C.sub.3-7-cycloalkyl-C(O)--OR.sup.1,
C.sub.3-7-cycloalkyl-OP(O)OR.sup.2OR.sup.2,
C.sub.3-7-cycloalkyl-P(O)OR.sup.2OR.sup.2,
C.sub.3-7-cycloalkyl-SO.sub.2OR.sup.2,
C.sub.3-7-cycloalkyl-PO.sub.3H,
(C.sub.1-6-alkyl)aryl-C(O)--OR.sup.1,
(C.sub.1-6-alkyl)aryl-OP(O)OR.sup.2OR.sup.2,
(C.sub.1-6-alkyl)aryl-P(O)OR.sup.2OR.sup.2,
(C.sub.1-6-alkyl)aryl-SO.sub.2OR.sup.2,
(C.sub.1-6-alkyl)aryl-PO.sub.3H, aryl-C(O)--OR.sup.1,
aryl-OP(O)OR.sup.2OR.sup.2, aryl-P(O)OR.sup.2OR.sup.2,
aryl-SO.sub.2OR.sup.2 and aryl-PO.sub.3H.
Exemplary embodiments of compounds of the formula II include
compounds of formula III as well compounds of the formula IIa-f,
wherein, in IIa-d, the Ar--C(O) moiety is fused into a bicyclic or
tricyclic system. Thus, an alternate embodiment of compounds of
formula II-ii is of the formula (Ar--C(O))-E-G-BN-L-A II-ii to
illustrate that the carbonyl is within the monocyclic or polycyclic
aromatic or heteroaromatic.
##STR00008##
A still further embodiment of the invention comprises compounds of
the formula II-iii, Ar--C(O)-G-BN-L-A II-iii wherein Ar--C(O) is an
arylketone, such as an amino arylketone. Exemplary aryl ketones
include benzodioxanyl ketones.
Suitable embodiments of compounds of formula II, A-C(O)-E-G-BN-L-A,
and IV include embodiments where A-C(O)-E is selected from the
group comprising of optionally substituted indole esters, isoindole
esters, indoline esters, indazole esters, benzimidiazole esters,
benzthiazole esters, purine estes, quinoline esters, isoquinoline
esters, cinnoline esters, carbazole esters and acridine esters.
An exemplary embodiment of compounds of formula II include
naphthalimides derivatized with a basic nitrogen and an acidic
moiety.
A and A-C(O) may be selected from any array of aromatic,
heteroaromatic or fused aromatic systems. Formulas II-e and II-f
are exemplary embodiments of compounds of formula III wherein
R.sup.9 and R.sup.10 form a ring system.
In a suitable embodiment of compounds of formula II,
A-C(O)-E-G-BN-L-A, the G-BN moiety forms a heterocyclic ring, such
as exemplified in compounds IIIa-d.
In a suitable embodiment of a compound of the of the formula I or
II is a compound of the formula III
##STR00009## wherein L-A is selected from the group consisting of
C.sub.2-6-alkyl-C(O)--OR.sup.1,
C.sub.2-6-alkyl-OP(O)OR.sup.2OR.sup.2,
C.sub.2-6-alkyl-P(O)OR.sup.2OR.sup.2,
C.sub.2-6-alkyl-SO.sub.2OR.sup.2, C.sub.2-6-alkyl-PO.sub.3H,
C.sub.3-7-cycloalkyl-C(O)--OR.sup.1,
C.sub.3-7-cycloalkyl-OP(O)OR.sup.2OR.sup.2,
C.sub.3-7-cycloalkyl-P(O)OR.sup.2OR.sup.2,
C.sub.3-7-cycloalkyl-SO.sub.2OR.sup.2,
C.sub.3-7-cycloalkyl-PO.sub.3H,
(C.sub.1-6-alkyl)aryl-C(O)--OR.sup.1,
(C.sub.1-6-alkyl)aryl-OP(O)OR.sup.2OR.sup.2,
(C.sub.1-6-alkyl)aryl-P(O)OR.sup.2OR.sup.2,
(C.sub.1-6-alkyl)aryl-SO.sub.2OR.sup.2,
(C.sub.1-6-alkyl)aryl-PO.sub.3H, aryl-C(O)--OR.sup.1,
aryl-OP(O)OR.sup.2OR.sup.2, aryl-P(O)OR.sup.2OR.sup.2,
aryl-SO.sub.2OR.sup.2 and aryl-PO.sub.3H; and E is selected from
the group consisting of O and NH; G is selected from the group
consisting of C.sub.1-6-alkyl, C.sub.3-7-cycloalkyl,
C.sub.1-6-alkyl-C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-6-alkyl; or wherein G-N together form
a C.sub.3-7-heteroalkyl, or a
C.sub.1-6-alkyl-C.sub.3-7-heteroalkyl; X is a halogen; R.sup.8 is
independently selected from H and C.sub.1-6-alkyl; R.sup.9 and
R.sup.10 are independently selected from the group consisting of H,
O--C.sub.1-6-alkyl, C.sub.1-6-alkyl, a C.sub.3-7-cycloalkyl, a
heterocycloalkyl, a heteroaryl, or an aryl; or wherein together
R.sup.9 and R.sup.10 form a C.sub.3-7-cycloalkyl, a
heterocycloalkyl, a heteroaryl, or an aryl; or wherein
NR.sup.8.sub.2 and R.sup.10 together form a heterocycloalkyl.
Compounds of the formula III may be, for instance, amino benzamide
derivatives or amino benzoates.
In a particularly interesting embodiment compounds of formula II, A
is selected from the group consisting of optionally substituted
benzyl, imidazopyridine, indole, isoindole, indoline, indazole and
benzimidazole.
Depending on the position of the basic nitrogen group, L may be
absent altogether and the acidic moiety may be directly linked to a
compound with 5-HT activity. An exemplary embodiment is compound
III-e but also compound III-d which can be seen as, in the
embodiment wherein L is a butyl chain, the acidic modification of
SB 204070 directly onto the alkyl chain.
In a typical embodiments of compounds of formula III, R.sup.10 is H
and R.sup.9 is O--C.sub.1-6-alkyl.
In another typical embodiment of compounds of formula III, R.sup.9
and R.sup.10 form a heterocyclic ring selected from the group
consisting of 1,4-dioxane, 1,3-dioxolane, pyridine, thiadiazole,
pyrrolidine, pyrroline, pyrrole, furan and piperidine.
##STR00010##
Exemplary embodiments of this aspect of the invention include
dihydrobenzofurans.
In an exemplary embodiment of III-c, n is 1, X is Cl, R.sup.8 are
H, R.sup.9 is OMe, R.sup.10 is H and R are each ethyl. Thus, the
embodiment is a derivative of metoclopamide wherein the terminal
ethylene groups of the tertiary ethylamine are modified with an
acidic moiety. This exemplary embodiment is a demonstrating of the
possibility of L being absent. In an alternate embodiment, only one
of the ethylene moieties are modified with an acidic moiety.
In a further exemplary embodiment, the invention defines
embodiments wherein Zacopride is modified with an acidic moiety
(III-b). In an interesting embodiment is of III-b, the acidic
moiety is bound directly to Zacopride, such as in III-e III-e
##STR00011##
A particularly interesting embodiment of compounds of formula III
includes cisapride and norcisapride, including optically active
forms thereof, each modified with an acidic moiety. Preferably,
when the acidic moiety is a carboxylic acid or ester attached to
the piperidinyl ring of cisapride or norcisapride, is preferably
not attached to the piperidinyl nitrogen but rather to a carbon on
the piperidinyl ring.
In a further interesting embodiment, in a compound of the of the
formula I or II, BN has the formula IV,
##STR00012## and L-A is selected from the group consisting of
C.sub.2-6-alkyl-C(O)--OR.sup.1,
C.sub.2-6-alkyl-OP(O)OR.sup.2OR.sup.2, C.sub.2-6-alkyl-P(O)OR
OR.sup.2, C.sub.2-6-alkyl-SO.sub.2OR.sup.2,
C.sub.2-6-alkyl-PO.sub.3H, C.sub.3-7-cycloalkyl-C(O)--OR.sup.1,
C.sub.3-7-cycloalkyl-OP(O)OR.sup.2OR.sup.2,
C.sub.3-7-cycloalkyl-P(O)OR.sup.2OR.sup.2,
C.sub.3-7-cycloalkyl-SO.sub.2OR.sup.2,
C.sub.3-7-cycloalkyl-PO.sub.3H,
(C.sub.1-6-alkyl)aryl-C(O)--OR.sup.1,
(C.sub.1-6-alkyl)aryl-OP(O)OR.sup.2OR.sup.2,
(C.sub.1-6-alkyl)aryl-P(O)OR.sup.2OR.sup.2,
(C.sub.1-6-alkyl)aryl-SO.sub.2OR.sup.2,
(C.sub.1-6-alkyl)aryl-PO.sub.3H, aryl-C(O)--OR.sup.1,
aryl-OP(O)OR.sup.2OR.sup.2, aryl-P(O)OR.sup.2OR.sup.2,
aryl-SO.sub.2OR.sup.2 and aryl-PO.sub.3H; E is selected from the
group consisting of O and NH; G is selected from the group
consisting of C.sub.1-6-alkyl, C.sub.3-7-cycloalkyl,
C.sub.1-6-alkyl-C.sub.3-7-cycloalkyl,
C.sub.3-7-cycloalkyl-C.sub.1-6-alkyl; or wherein G-N together form
a C.sub.3-7-heteroalkyl, or a
C.sub.1-6-alkyl-C.sub.3-7-heteroalkyl; and wherein the
##STR00013## moiety is selected from the group consisting of an
oxazinoindole,
##STR00014## wherein X is absent or a halogen; R.sup.13 is selected
from the group consisting of H, NH.sub.2, and C.sub.1-6-alkyl; and
R.sup.14 and R.sup.15 are independently selected from the group
consisting of H, and C.sub.1-6-alkyl; or wherein R.sup.14 and
R.sup.15 together from a C.sub.3-7-cycloalkyl or a
C.sub.3-7-heterocycle. Suitably, R14 and R15 form a
tetrahydropyran.
In a preferred embodiment wherein of compounds of formula IV, the
ester is covalently linked to the heterocycle. In a most preferred
embodiment, the ester is covalently linked to the .alpha.-carbon or
other .alpha.-atom, such as the heteroatom .alpha.-situated from
the aryl ring.
Exemplary embodiments of compounds of formula IV include indole and
indoline esters and amides of the formula IVa-d.
##STR00015## wherein n is an whole number selected from 0-10, such
as 1, 2, 3, 4, 5, 6, 7 8, 9, and 10.
As stated, in a most preferred embodiment of compounds of formula
II, Ar is selected from the group consisting of phenyl naphthalene,
indole, benzodioxane, indazole, and oxazinoindole. The present
inventors have found compounds of formula II comprising an
oxazinoindole to be rather interesting, such as compound IV-d.
In a particularly interesting embodiment, the compound of formula
II is a derivative of piboserod, namely of the formula IV-P
##STR00016## wherein L is absent or selected from the group
consisting of straight chain or branched optionally substituted
C.sub.1-10-alkyl, optionally substituted C.sub.2-10-alkenyl,
optionally substituted C.sub.2-10-alkynyl, C.sub.1-10-alkylamine,
C.sub.1-10-alkoxy, C.sub.2-10-alkenyloxy, C.sub.2-10-alkynyloxy,
C.sub.1-10-alkoxycarbonyl, C.sub.2-10-alkenyloxycarbonyl,
C.sub.2-10-alkynyloxycarbonyl or combinations thereof; and A is
selected from the group consisting of C(O)--OR.sup.1,
OP(O)OR.sup.2OR.sup.2, P(O)OR.sup.2OR.sup.2, SO.sub.2OR.sup.2,
SO.sub.3H, OSO.sub.3H, and PO.sub.3H; wherein R.sup.1 and R.sup.2
are independently selected from the group consisting of H, M,
C.sub.1-15-alkyl, C.sub.3-8-cycloalkyl, aryl, and R.sup.1,2 wherein
R.sup.1,2 is R'--O--C(O)--R'', R'--O--C(O)--O--R'',
R'--C(O)--O--R'', wherein R' and R'' are independently selected
from the group consisting of C.sub.1-15-alkyl, C.sub.3-8-cycloalkyl
and aryl; R.sup.13 is selected from the group consisting of H,
halogen, NH.sub.2, and C.sub.1-6-alkyl; and R.sup.16 is selected
from the group consisting of H, halogen, OH, O--C.sub.1-6-alkyl,
and C.sub.1-6-alkyl.
L is typically selected from straight chain or branched optionally
substituted C.sub.1-10-alkyl, C.sub.1-10-alkoxycarbonyl,
C.sub.1-10-alkylamine or C.sub.1-10-alkoxy. In embodiments wherein
L is a branched chain optionally substituted C.sub.1-10-alkyl,
C.sub.1-10-alkylamine or C.sub.1-10-alkoxy, there may be one or two
acidic moieties A, namely L-A may be of the formula
##STR00017## where X is selected from the group consisting of C and
N and i, j, and k are independently selected from a whole number
selected from the group consisting of 0-10, wherein the sum i+j+k
is typically less than 10; and one or both of the A groups is as
defined above, the other being absent.
An exemplary embodiment of branched optionally substituted
C.sub.1-10-alkyl, C.sub.1-10-alkoxycarbonyl, C.sub.1-10-alkylamine
or C.sub.1-10-alkoxy is
##STR00018##
In a most preferred embodiment of compounds of the formula IV-P,
L-A is selected from the group consisting of a straight chain
C.sub.1-10-alkyl-CO.sub.2H, a straight chain
C.sub.1-10-alkyl-C(O)--OR.sup.1, a branched
C.sub.1-10-alkyl-CO.sub.2H, a branched
C.sub.1-10-alkyl-C(O)--OR.sup.1 and di(C.sub.1-10-alkoxycarbonyl)s
of the formula
C.sub.1-10-alkyl-C(O)O--CH(C.sub.1-10-alkyl)-OC(O)O--C.sub.1-10-alkyl,
C.sub.1-10-alkyl-C(O)O--CH(C.sub.1-10-alkyl)-C(O)O--C.sub.1-10-alkyl,
and
C.sub.1-10-alkyl-C(O)O--CH(C.sub.1-10-alkyl)-OC(O)--C.sub.1-10-alkyl.
A further interesting embodiment of compounds having i) a binding
affinity to a 5-HT receptor with a pK.sub.i of at least 5; ii)
comprises at least one basic nitrogen atom; iii) comprises at least
one acidic moiety with a pKa of no more than 6.4, or a salt or
ester thereof; and iv) an aromatic or heteroaromatic ring, more
typically an aromatic ring is a compound of formula V
##STR00019## wherein L-A is selected from the group consisting of
C.sub.2-6-alkyl-C(O)--OR.sup.1,
C.sub.2-6-alkyl-OP(O)OR.sup.2OR.sup.2,
C.sub.2-6-alkyl-P(O)OR.sup.2OR.sup.2,
C.sub.2-6-alkyl-SO.sub.2OR.sup.2, C.sub.2-6-alkyl-PO.sub.3H,
C.sub.3-7-cycloalkyl-C(O)--OR.sup.1,
C.sub.3-7-cycloalkyl-OP(O)OR.sup.2OR.sup.2,
C.sub.3-7-cycloalkyl-P(O)OR.sup.2OR.sup.2,
C.sub.3-7-cycloalkyl-SO.sub.2OR.sup.2,
C.sub.3-7-cycloalkyl-PO.sub.3H,
(C.sub.1-6-alkyl)aryl-C(O)--OR.sup.1,
(C.sub.1-6-alkyl)aryl-OP(O)OR.sup.2R.sup.2,
(C.sub.1-6-alkyl)aryl-P(O)OR.sup.2OR.sup.2,
(C.sub.1-6-alkyl)aryl-SO.sub.2OR.sup.2,
(C.sub.1-6-alkyl)aryl-PO.sub.3H, aryl-C(O)--OR.sup.1,
aryl-OP(O)OR.sup.2OR.sup.2, aryl-P(O)OR.sup.2OR.sup.2,
aryl-SO.sub.2OR.sup.2 and aryl-PO.sub.3H; Z is an integer selected
from the group consisting of 0, 1, and 2, and wherein the aromatic
bicyclic ring
##STR00020## moiety is selected from the group consisting of
##STR00021## wherein R.sup.13 is selected from the group consisting
of H, NH.sub.2, and C.sub.1-6-alkyl; R.sup.14 and R.sup.15 are
independently selected from the group consisting of H, and
C.sub.1-6-alkyl; or
R.sup.14 and R.sup.15 together from a C.sub.3-7-cycloalkyl or a
C.sub.3-7-heterocycle; and R.sup.16 is selected from the group
consisting of H, OH, O--C.sub.1-6-alkyl, and C.sub.1-6-alkyl.
Compounds of formula V will be recognised by the skilled artisan as
derivatives of compounds of the formula II, namely the aryl ketones
of formula II-iii, A-C(O)-G-BN-L-A.
Further interesting embodiments of the aromatic bicyclic ring may
be selected from the group comprising indene, naphthalene,
coumaran, benzofuran, azulene, indole, isoindole, indoline,
indazole, benzimidiazole, benzthiazole, purine, quinoline,
isoquinoline, cinnoline, carbazole, and acridine.
An exemplary embodiment of compounds of the formula V include
compound V-a
##STR00022##
A particularly interesting embodiment of the invention relates to
derivatives of tegaserod
##STR00023## wherein the aliphatic chain is derivatized to comprise
an acidic moiety and optional modification of the bicyclic
aromatic. An interesting embodiment of the invention is a compound
of formula VI,
##STR00024## wherein X and Y are independently selected from the
group consisting of NH, O, C, and S; L is absent or selected from
the group consisting of straight chain or branched optionally
substituted C.sub.1-10-alkyl, optionally substituted
C.sub.2-10-alkenyl, optionally substituted C.sub.2-10-alkynyl,
C.sub.1-10-alkylamine, C.sub.1-10-alkoxy, C.sub.2-10-alkenyloxy,
C.sub.2-10-alkynyloxy, C.sub.1-10-alkoxycarbonyl,
C.sub.2-10-alkenyloxycarbonyl, C.sub.2-10-alkynyloxycarbonyl or
combinations thereof; A is selected from the group consisting of
C(O)--OR.sup.1, OP(O)OR.sup.2OR.sup.2, P(O)OR.sup.2OR.sup.2,
SO.sub.2OR.sup.2, SO.sub.3H, OSO.sub.3H, and PO.sub.3H; wherein
R.sup.1 and R.sup.2 are independently selected from the group
consisting of H, M, C.sub.1-15-alkyl, C.sub.3-8-cycloalkyl, aryl,
and R.sup.1,2 wherein R.sup.1,2 is R'--O--C(O)--R'',
R'--O--C(O)--O--R'', R'--C(O)--O--R'', wherein R' and R'' are
independently selected from the group consisting of
C.sub.1-15-alkyl, C.sub.3-8-cycloalkyl and aryl; and R.sup.16 and
R.sup.13 are independently selected from the group consisting of H,
OH, halogen, NH.sub.2, O--C.sub.1-6-alkyl, and C.sub.1-6-alkyl.
L is suitably selected from straight chain or branched optionally
substituted C.sub.1-10-alkyl, C.sub.1-10-alkoxycarbonyl,
C.sub.1-10-alkylamine or C.sub.1-10-alkoxy. In embodiments wherein
L is a branched chain optionally substituted C.sub.1-10-alkyl,
C.sub.1-10-alkylamine or C.sub.1-10-alkoxy, there may be one or two
acidic moieties A, namely L-A may be of the formula
##STR00025## where X is selected from the group consisting of C and
N and i, j, and k are independently selected from a whole number
selected from the group consisting of 0-10 (wherein the sum i+j+k
is typically less than 10; and one or both of the A groups is as
defined above, the other being absent. An exemplary embodiment of
branched optionally substituted C.sub.1-10-alkyl,
C.sub.1-10-alkylamine or C.sub.1-10-alkoxy is
##STR00026##
In a highly suitable embodiment, L is a straight chain or branched
optionally substituted C.sub.1-10-alkyl.
Preferably, A is selected from the group consisting of
--C(O)--OR.sup.1, and --P(O)OR.sup.2OR.sup.2, wherein R.sup.1 and
R.sup.2 are independently selected from the group consisting of H,
M, C.sub.1-15-alkyl, C.sub.3-8-cycloalkyl, and aryl. Particularly
interesting are the carboxylic acids or their C.sub.1-6-alkyl
esters, such as their methyl esters, ethyl esters, and
trichloroethyl esters
In a preferred embodiment of compounds of formula VI, R.sup.16 is
selected from the group consisting of H, OH, O--C.sub.1-6-alkyl,
and C.sub.1-6-alkyl; and R.sup.13 is selected from the group
consisting of H, NH.sub.2, and C.sub.1-6-alkyl. More preferably,
R.sup.16 is O--C.sub.1-6-alkyl, most preferably O--CH.sub.3.
As stated, the compounds of the invention are 5-HT modulators,
typically 5-HT4 modulators. In a suitable embodiment, the compounds
of the invention are 5-HT4 agonists. In a further suitable
embodiment, the compounds of the invention are 5-HT4 antagonists.
In a still further suitable embodiment of the invention, the
compounds of the invention are partial agonists.
The subject invention provides novel compounds and compositions for
the safe and effective treatment of gastroesophageal reflux and
related conditions. These compositions possess potent activity in
treating gastroesophageal reflux disease and substantially reduce
adverse effects associated with the administration of 5-HT
modulators. These adverse effects include, but are not limited to,
diarrhea, abdominal cramping and elevations of blood pressure and
heart rate.
The compounds of the invention are anticipated are intended for
treatment of dyspepsia, gastroparesis, constipation, post-operative
ileus, and intestinal pseudo-obstruction. Dyspepsia is a condition
characterized by an impairment of the power or function of
digestion that can arise as a symptom of a primary gastrointestinal
dysfunction or as a complication due to other disorders such as
appendicitis, gallbladder disturbances, or malnutrition.
Gastroparesis is a paralysis of the stomach brought about by a
motor abnormality in the stomach or as a complication of diseases
such as diabetes, progressive systemic sclerosis, anorexia nervosa
or myotonic dystrophy. Constipation is a condition characterized by
infrequent or difficult evacuation of feces resulting from
conditions such as lack of intestinal muscle tone or intestinal
spasticity. Post-operative ileus is an obstruction in the intestine
due to a disruption in muscle tone following surgery. Intestinal
pseudo-obstruction is a condition characterized by constipation,
colicky pain, and vomiting, but without evidence of physical
obstruction.
An important aspect of the invention relates to a method of
treating a cardiovascular disorder comprising administering a
compound having a binding affinity to a 5-HT receptor with a
pK.sub.i of at least 5; ii) comprises at least one basic nitrogen
atom; iii) comprises at least one acidic moiety with a pKa of no
more than 6.4, or a salt or ester thereof. This method treating a
cardiovascular disorder is done essentially free of CNS-related
side effects. Typically, the compound having a binding pK.sub.i for
a 5-HT receptor of at least 5, said compound comprising a molecular
skeleton of the formula I BN-L-A wherein BN is a basic nitrogen
moiety; and -A is an acidic moiety with a pKa of no more than 6.4
or an ester thereof; wherein BN-L-A comprises at least 3
consecutive chemical bonds between BN and the acidic moiety.
In an exemplary embodiment of treating a cardiovascular disorder,
the disorder is selected from the group consisting of tachycardia,
bradycardia, cardioexcitation, cardiodepression, arrhythmia,
fibrillation, atrial fibrillation, Paroxysmal Supraventricular
Tachycardia (PSVT), thromoembolisms and VTE.
A further aspect of the invention relates to a method of treating
gastrointestinal disorders comprising administering a compound of
the invention. In exemplary embodiments of this aspect of the
invention, the gastrointestinal disorder is selected from the group
consisting of irritable bowel syndrome, gastrointestinal
hypomotility disorders such as gastro-esophageal reflux (heartburn,
mild oesophagitis); functional or nonulcer dyspensia;
gastroparesis, nausea and vomiting; early satiety in the elderly;
paraneoplastic of HIV-associated gastroparesis; drug-induced delays
in gastric emptying and functional bowel obstructions, such as
bowel obstructions caused by pancreatic cancer or drugs; and
emesis.
A further aspect of the present invention includes a method of
treating a condition caused by gastrointestinal motility
dysfunction in a mammal which comprises administering to a mammal
in need of treatment for gastrointestinal motility dysfunction, a
therapeutically effective amount of a compound of the invention or
a pharmaceutically compositions thereof. Conditions caused by
gastrointestinal motility dysfunction include, but are not limited
to, dyspepsia, gastroparesis, constipation, post-operative ileus,
and intestinal pseudo-obstruction. Preferably, the mammal is a
human.
In the treatment of treating gastrointestinal disorders or
gastrointestinal motility dysfunction, the inventors disclaim, as
such, compounds of the formula
##STR00027## wherein R is selected from H, methyl, ethyl,
isopropyl, sec-butyl, and 4-fluorophenyl and n is 0, 1, 2, 3, or 4.
More typically, the inventors herein disclaim In the treatment of
treating gastrointestinal disorders or gastrointestinal motility
dysfunction, wherein n is from 0 to 8 and R is hydrogen, lower
alkyl, or substituted aryl.
A further aspect of the invention relates to a method of treating
lower urinary tract disorders, such as e.g. hyperactive bladder,
comprising administering a compound of the invention.
The treatment of primary or secondary hyperaldosteronism comprising
administering a compound of the invention is a further aspect of
the invention. The person skilled in the art will appreciate that
the compounds of the invention are applicable for use in the
treatment of all diseases associated with peripheral 5-HT
receptors. Thus, a further aspect of the invention relates to a
method of treating a disease associated, at least in part, with a
peripheral 5-HT receptor subgroup comprising administering a
compound of the invention. Pharmacologically the active principle
according to the invention has the advantage of facilitating
absorption over the gastrointestinal membranes due to the
relatively lipophilic moiety and/or nonionic moiety, such as an
ester group. Subsequently to being absorbed through the biomembrane
of the gastrointestinal tract the facilitating moiety is cleavaged
from the active principle resulting in leaving an acid moiety on
the active principle. The active principle comprising the acid
moiety is then present in the blood circulation for systemic
action. As a consequence of the residual acid moiety the access to
the brain over the BBB is prevented.
Thus the active principle is in one aspect of the invention acting
as a pro-drug facilitating the absorption over the biomembrane of
the gastrointestinal tract. A further aspect of the invention
relates to the systemically circulating drug that is provided with
an moiety, such as an acid moiety, that prevents the absorption
over the BBB.
In embodiments of the invention wherein known compounds are
modified according to the invention, that is to say with an acidic
moiety, the compounds of this invention are anticipated to have
therapeutic properties similar to those of the unmodified parent
compounds. Accordingly, dosage rates and routes of administration
of the disclosed compounds are similar to those already used in the
art and known to the skilled artisan (see, for example, Physicians'
Desk Reference, 54th Ed., Medical Economics Company, Montvale,
N.J., 2000).
Typically doses of compounds of formula III will be from about 0.1
mg to about 200 mg, in single or divided doses. Preferably, a daily
dose range should be between about 1 mg to about 100 mg, in single
or divided doses, while most preferably, a daily dose range should
be between about 2 mg to about 75 mg, in single or divided doses.
It is preferred that the doses are administered from 1 to 4 times a
day. It may be necessary to use dosages outside these ranges in
some cases as will be apparent to those skilled in the art.
A further aspect of the invention relates to a composition
comprising a compound of the invention and a pharmaceutically
acceptable excipient. The compounds of the subject invention can be
formulated according to known methods for preparing
pharmaceutically useful compositions. Formulations are described in
detail in a number of sources which are well known and readily
available to those skilled in the art. For example, Remington's
Pharmaceutical Science by E. W. Martin describes formulations which
can be used in connection with the subject invention. In general,
the compositions of the subject invention are formulated such that
an effective amount of the bioactive compound(s) is combined with a
suitable carrier in order to facilitate effective administration of
the composition.
In one embodiment of the invention the active component is
formulated in a pharmaceutical dosage unit. The dosage unit can be
formulated for release of the active principle in the stomach. The
dosage unit can be formulated for release of the active principle
in the duodenum. The dosage unit can be formulated as a sustained
release formulation, implying that the active principle is not
immediately released. The release can be sustained to take place in
the intestinal tract. In one embodiment the sustained release can
take place in the small intestine. In a suitable embodiment, the
sustained release takes place in the colon.
The dosage unit comprises pharmaceutically acceptable excipients.
The dosage unit is typically a tablet or capsule. The dosage unit
can be coated with an exipient known in the art for controlling the
disintegration of the dosage unit. Such coating excipients
comprises one or more of various polymers such as
polymethacrylates, tributylesters, cellulose and modified
celluloses, carboxymethylcellulose and salts thereof, natural and
synthetic waxs, carnaubawax, polyvinylpyrrolidone, sugar alcohols,
starch and modified starch, gelatine, chitosan and shellac though
is not limited hereto.
In still another embodiment the release is controlled in a manner
that implies for a targeted release. The dosage unit formulated as
a targeted release formulation can control the release to take
place at the desired site of action. The release can be controlled
in a manner where a burst dose of the active principle is initially
released, followed by a secondary release at a later time point
and/or at another site in the gastrointestinal tract. The release
can be controlled by means of pH as the pH varies in the
gastrointestinal tract. Alternatively, the release can be
controlled by a dosage unit that is eroded in a time dependent
manner. In one embodiment the dosage unit is formulated to have a
prolonged release, by which is intended that the active principle
is slowly released over a longer time period compared with that of
an immediate release dosage unit.
The sustained or controlled release effect can be achieved by a
coating or by a matrix type of dosage unit, as is well-known in the
art.
In one embodiment the tablet is a matrix type of tablet. In another
embodiment the tablet is coated.
In still another embodiment the active principle is formulated to
give a fast onset of action. The fast onset of action can be
achieved by formulating the dosage unit in formulations that
implies absorption of the active principle transmucosally. In one
aspect the active principle is formulated into a buccal formulation
providing the active principle to buccal absorption. A buccal
formulation comprises a tablet, a sublingual tablet, a buccal
patch, a buccal spray, a chewing gum.
Administration routes like nasal, transdermal and buccal
administration have special advantages when treating conditions
implying nausea and/or vomiting.
One embodiment of the invention relates to formulating the active
principle into a formulation for nasal administration. By the nasal
administration is intended a systemic action. Though administering
the active principle nasally, the intention being to treat
conditions peripherally and not for the active principle to cross
the blood-brain-barrier. Nasal administration has the advantage of
a fast onset of action. However, nasal administration is also known
to provide direct access to the CNS, which is to be avoided when
targetting peripheral 5-HT, particularly 5-HT4 receptors.
As can be realised by the artisan, the chemical characteristics of
the active substance are such that the compound has one lipophilic
site and one hydrophilic site of the molecule. The lipophilic part
will tend to be readily absorbed into biological membranes. The
hydrophilic part will in the circumstances that it is ionised not
be readily absorbed through biological membranes. In the embodiment
where the hydrophilic end comprises an acid moiety, the acid moiety
will be non-ionised in an environment more acidic than the pKa
value. In the embodiment where the hydrophilic site comprises a
basic moiety the basic moiety will be unionised in an environment
more basic than the pKa value.
In the embodiment where the hydrophilic site comprises a acid
moiety the artisan will often prefer to formulate the active
principle as the salt of the acid. This will also be the case in
the event that the hydrophilic site comprises a basic moiety.
Formulating the active principle as a salt can improve the
solubility and the solubility rate. Pharmaceutical salts of basic
active principles are salts of strong or medium strong acids;
hydrochloric acid; sulphate; phosphate or weak acids like tartrate;
acetate etc. Salts of weak acids are typically salts of sodium;
potassium; or calcium.
In one embodiment the active principle is formulated in a
formulation comprising lipid excipients. The lipid excipients are
providing compositions wherein the active principle of the
invention is encapsulated. By formulating the active principle in a
lipid formulation the absorption over the biological membrane of
the intestinal tract is facilitated. Once absorbed systemically the
active principle will be released from the lipid formulation. The
active principle will target itself to the desired site of action
while being hindered to pass the BBB due to the character, such as
an ionic character, of the hydrophilic moiety. In preparing the
lipid formulations, lipid components including neutral lipids,
positively-charged lipids, such as sphingosine and ceramide,
negatively-charged lipids, amphoteric lipids such as phospholipids,
and cholesterol are advantageously used. As defined herein, the
"lipid component" of the compositions of the invention are intended
to encompass a single species of lipid (such as a particular
phospholipid) or combinations of such lipids, either of one type
such as combinations of phospholipids (for example,
phophatidylcholine plus phosphatidyl enthanolamine) or of different
types (such as a phospholipid plus a charged lipid or a neutral
lipid). Combinations comprising a multiplicity of different lipid
types are also advantageously encompassed by the proliposomal
compositions of the invention.
Chemical substances crosses the blood brain barrier (BBB) via
differents routes such as opening of tight junctions, increased
pinocytosis, decreased membrane rigidity, by pore formation or
other mechanisms. There are four basic mechanisms by which solute
molecules move across membranes. First is by simple diffusion,
which proceeds from low to high concentrations. Secondly is by
facilitated diffusion, a form of carrier-mediated endocytosis, in
which solute molecules bind to specific membrane protein carriers,
also from low to high concentration. Thirdly is simple diffusion
through an aqueous channel, formed within the membrane. Fourthly is
by active transport through a protein carrier with a specific
binding site that undergoes a change in affinity. Active transport
requires ATP hydrolysis and conducts movement against the
concentration gradient. Movement between cells is referred to as
paracellular diffusion. The BBB has a number of highly selective
mechanisms for transport of nutrients into the brain.
Diffusion of substances into the brain can be divided into
paracellular (i.e. between cells) and transcellular.sub.13(i.e.
across cells) diffusion, both of which are non-saturable and
non-competitive. Paracellular diffusion does not occur to any great
extent at the BBB, due to the "tight junctions". In the case of
transcellular diffusion, the general rule is the higher the
lipophilicity of a substance, the greater the diffusion into the
brain. Another general rule is the smaller size of the molecule the
greater the diffusion into the brain. In the present invention the
active principle is chemically modified comprising a polar site
that prevents the active principle from being transported into the
brain. Further the transportation through the BBB can be prevented
by modifying the active principle with a bulky moiety as the BBB is
most permeable towards small, lipid-soluble molecules.
The compositions of the subject invention include compositions such
as suspensions, solutions and elixirs; aerosols; or carriers such
as starches, sugars, microcrystalline cellulose, diluents,
granulating agents, lubricants, binders, disintegrating agents, and
the like, in the case of oral solid preparations (such as powders,
capsules, and tablets) with the oral solid preparations being
preferred over the oral liquid preparations. A preferred oral solid
preparation is capsules. The most preferred oral solid preparation
is tablets. Further, acceptable carriers can be either solid or
liquid. Solid form preparations include powders, tablets, pills,
capsules, cachets, suppositories and dispersible granules. A solid
carrier can be one or more substances which may act as diluents,
flavoring agents, solubilizers, lubricants, suspending agents,
binders, preservatives, tablet disintegrating agents or
encapsulating materials.
The pharmaceutical compositions may be subdivided into unit doses
containing appropriate quantities of the active component. The unit
dosage form can be a packaged preparation, such as packeted
tablets, capsules, and powders in paper or plastic containers or in
vials or ampules. Also, the unit dosage can be a liquid based
preparation or formulated to be incorporated into solid food
products, chewing gum, or lozenge.
Any suitable route of administration may be employed for providing
the patient with an effective dosage. For example, oral, rectal,
parenteral (subcutaneous, intramuscular, intravenous), transdermal,
and like forms of administration may be employed. Dosage forms
include tablets, troches, dispersions, suspensions, solutions,
capsules, patches, and the like.
When formulating the active principle into a transdermal
formulation special care should be taken to select a suitable
enhancer.
One aspect of the invention relates to formulating the active
principle into a dosage unit that displays a stability that implies
a shelf-life of the dosage units of 5 years; such as 4 years; such
as 3 years; such as 2 years. In one embodiment the stability during
the shelf-life is obtained by means of the packaging material. In
one embodiment packaging material displays a high resistance
towards water vapour.
One embodiment of the invention provides a method of treating
gastroesophageal reflux disease in a mammal, while substantially
reducing the concomitant adverse effects associated with the
administration of the compound devoid of the acidic moiety,
comprising administering to a human in need of such treatment, a
therapeutically effective amount of a compound of the
invention.
Yet another embodiment of the present invention provides a method
of eliciting an anti-emetic effect in a mammal, while substantially
reducing the adverse effects associated with the administration of
the compound devoid of the acidic moiety, comprising administering
to a mammal in need of such anti-emetic therapy, a therapeutically
effective amount a compound of the invention.
Without being limited to examples, the invention is further
directed to any one of the compounds described in the examples,
having an acidic moiety and/or esters thereof. Table 1 in the
Examples demonstrate the proof of concept that a representative
sample of all of the compounds of the invention have a good binding
affinity for the serotonin receptor.
EXAMPLES
Synthetic Chemistry
Example 1
Preparation of intermediate 2,2,2-trichloroethyl
4-bromobutyrate
##STR00028##
A stirred solution of 4-bromobutyric acid (3.34 g, 20.0 mmol) in
toluene (50 ml) was added 2,2,2-trichloroethanol (14.94 g, 0.10
mol) and p-toluenesulfonic acid monohydrate (7.60 g, 40.0 mmol) and
refluxed with a Dean-Stark trap attached for 6 h. Water was removed
continuously. The reaction mixture was cooled to room temperature
and concentrated in vacuo. The mixture was added CH.sub.2Cl.sub.2
(75 ml) and washed with H.sub.2O (3.times.25 ml). The organic layer
was dried over Na.sub.2SO.sub.4, filtered and evaporated in vacuo
to leave an oil. The residue was distilled to leave the title
compound as a colourless oil (4.77 g, 79.9%) (bp 100.degree. C. at
0.5 mmHg).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 4.74 (s, 2H), 3.48 (t, 2
H), 2.65 (t, 2 H), 2.21-2.13 (m, 2 H)
Example 2
Preparation of intermediate
4-(4-hydroxymethyl-piperidin-1-yl)butyric acid
2,2,2-trichloroethylester
##STR00029##
A stirred solution of 4-piperidinemethanol (1.72 g, 15.0 mmol) in
acetone (100 ml) was added K.sub.2CO.sub.3 (4.14 g, 30. mmol) and
2,2,2-trichloroethyl 4-bromobutyrate (4.47 g, 15.0 mmol) and heated
under reflux for 3 h. The reaction mixture was cooled to room
temperature, filtered and the filtrate concentrated in vacuo. The
residue was added CH.sub.2Cl.sub.2 (75 ml) and washed with brine
(25 ml) and H.sub.2O (2.times.25 ml). The organic layer was dried
over Na.sub.2SO.sub.4, filtered and evaporated in vacuo to leave
the title compound as a viscous oil (4.70 g, 94.1%).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 4.74 (s, 2H), 3.50 (d, 2
H), 2.92 (d, 2 H), 2.52-2.35 (m, 4 H), 1.97-1.70 (m, 7 H),
1.52-1.45 (m, 1 H), 1.32-1.23 (m, 2 H)
Example 3
Synthesis of 1H-indole-3-carboxylic acid
1-[3-(2,2,2-trichloroethyl-ethoxycarbonyl)-propyl]-piperidine-4-ylmethyl
ester
##STR00030##
A suspension of indole-3-carboxylic acid (2.90 g, 18.0 mmol) in
CH.sub.2Cl.sub.2 (75 ml) was treated with oxalyl chloride (1.84 ml,
20.7 mmol) and DMF (1 drop) and the mixture stirred at room
temperature for 2 h, then concentrated in vacuo to leave the acid
chloride as a yellow solid. This was dissolved in a mixture of
CH.sub.2Cl.sub.2 (30 ml) and THF (10 ml) and added dropwise (30
min) to a stirred solution of
4-(4-hydroxymethyl-piperidin-1-yl)butyric acid 2,2,2-trichloroethyl
ester (from example 2) (4.98 g, 15.0 mmol) and NEt.sub.3 (1.82 g,
18.0 mmol) in CH.sub.2Cl.sub.2 (30 ml). The reaction mixture was
stirred at room temperature overnight, treated with an aqueous
satd. NaCl solution (25 ml) and 10% aqueous NaHCO.sub.3 solution
(25 ml). The organic layer was dried over Na.sub.2SO.sub.4,
filtered and evaporated in vacuo to a brown viscous oil. The
residue was separated with flash chromatography (SiO.sub.2, EtOAc).
The product was obtained as a pale yellow solid (1.83 g, 25.6%).
Conversion to the hydrochloride salt was effected using etheral
HCl.
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.02 (br s, 1 H),
8.22-8.18 (m, 1 H), 7.92 (d, 1 H), 7.48-7.41 (m, 1 H), 7.35-7.28
(m, 2 H), 4.77 (s, 2 H), 4.24 (d, 2 H) 3.03 (d, 2 H), 2.59-2.44 (q,
5 H), 2.13-1.85 (m, 7 H), 1.60-1.43 (m, 2 H)
.sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 171.7, 165.5, 136.2,
131.5, 125.7, 122.8, 121.7, 121.0, 111.7, 108.0, 94.8, 73.7, 67.9,
57.5, 53.1, 35.4, 31.7, 28.8, 21.8
MS (ES): 477.1 [M+H].sup.+
Example 4
Synthesis of 1H-indole-3-carboxylic acid
1-(3-carboxy-propyl)-piperidin-4-ylmethyl ester
##STR00031##
1H-indole-3-carboxylic acid
1-[3-(2,2,2-trichloroethyl-ethoxycarbonyl)-propyl]piperidine-4-ylmethyl
ester (0.48 g, 1.0 mmol) was dissolved in a mixture of THF (25 ml)
and aqueous 1 M KH.sub.2PO.sub.4 (5 ml). Zn-powder (0.66 g, 10.0
mmol) was added and the resulting mixture stirred at room
temperature for 24 h. The reaction mixture was filtered through a
pad of kiselguhr and the filtrate evaporated in vacuo. The residue
was separated with flash chromatography (SiO.sub.2, EtOAc/MeOH
(2:1)). The expected product was obtained as a white solid (0.29 g,
84.2%). Conversion to the hydrochloride salt was effected using
etheral HCl.
.sup.1H-NMR (300 MHz, DMSO): .delta. 11.98 (s, 1 H), 8.08-7.97 (m,
2 H), 7.47 (d, 1 H), 7.20-7.17 (m 2 H), 4.11 (d, 2 H), 2.96 (d, 2
H), 2.50-2.37 (m, 4 H), 2.05 (t, 2 H), 1.77-1.66 (m, 6 H),
1.42-1.35 (m, 2 H)
.sup.13C-NMR (75 MHz, DMSO): .delta. 171.7, 165.5, 136.2, 131.5,
125.7, 122.8, 121.7, 121.0, 111.7, 108.0, 94.8, 73.7, 67.9, 57.5,
53.1, 35.4, 31.7, 28.8, 21.8
MS (ES): 345.2 [M+H].sup.+
Example 5
Preparation of intermediate N-(1-benzylpiperidin-4-yl)napth-1-yl
carboxamide
##STR00032##
A stirred suspension of 1-napthoic acid (8.61 g, 0.050 mol) in
CH.sub.2Cl.sub.2 (150 ml) was added SOCl.sub.2 (23.79 g, 0.20 mol)
and the mixture heated under reflux for 4 h. The mixture was
evaporated in vacuo to leave the acid chloride as a solid material.
This was dissolved in CH.sub.2Cl.sub.2 (150 ml) and added dropwise
to a stirred solution of 4-amino-1-benzylpiperidine (9.51 g, 0.050
mol) and NEt.sub.3 (5.06 g, 0.05 mol) in CH.sub.2Cl.sub.2 (100 ml)
at 0.degree. C. The mixture was stirred to room temperature for 24
h and washed with H.sub.20 (3.times.75 ml) The organic layer was
dried over Na.sub.2SO.sub.4 and evaporated in vacuo to a solid
material. This was recrystallized from ethanol/water (40/60) to
leave the product as a white solid (7.8 g, 45.3%).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 8.32-8.27 (m, 1 H), 7.90
(t, 2 H), 7.57-7.30 (m, 9 H), 6.17 (d, 2 H), 4.17-4.06 (m, 1 H),
3.55 (s, 2H), 2.88 (d, 2 H), 2.27-2.05 (m, 4 H), 1.69-1.50 (m, 2
H)
Example 6
Preparation of intermediate N-(piperidin-4-yl)napth-1-yl
carboxamide hydrochloride
##STR00033##
A solution of N-(1-benzylpiperidin-4-yl)napth-1-yl carboxamide
(1.38 g, 4.0 mmol) in dry CH.sub.2Cl.sub.2 (15 ml) was cooled to
0.degree. C. and added .alpha.-chloroethyl chloroformate (1.14 g,
8.0 mmol) and stirred for 30 minutes. The mixture was evaporated in
vacuo, added MeOH (15 ml) and heated under reflux for 1 h. The
reaction mixture was evaporated in vacuo and the residue
recrystallized from acetonitrile to give the product as a white
powder (1.01 g, 86.8%).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 8.32-8.27 (m, 1 H), 7.90
(t, 2 H), 7.57-7.30 (m, 9 H), 6.17 (d, 2 H), 4.17-4.06 (m, 1 H),
3.55 (s, 2H), 2.88 (d, 2 H), 2.27-2.05 (m, 4 H), 1.69-1.50 (m, 2
H)
Example 7
Alkylation of N-(piperidin-4-yl)napth-1-yl carboxamide
hydrochloride with 2,2,2-trichloroethyl 4-bromobutyrate
##STR00034##
A stirred suspension of N-(piperidin-4-yl)napth-1-yl carboxamide
hydrochloride (0.58 g, 2.0 mmol) in acetone (20 ml) was added
K.sub.2CO.sub.3 (1.10 g, 8.0 mmol) and 2,2,2-trichloroethyl
4-bromobutyrate-(0.89 g, 3.0 mmol) and heated under reflux for 24
h. The mixture was cooled to room temperature and filtered. The
filtrate was evaporated in vacuo and the residue added
CH.sub.2Cl.sub.2 (50 ml) and washed with H.sub.20 (3.times.25 ml).
The organic layer was dried over Na.sub.2SO.sub.4, filtered and
evaporated in vacuo to an oil. The oil was separated with flash
chromatography (SiO.sub.2, EtOAc/MeOH (1:1)) to give the product as
a white solid (0.87 g, 92.2%).
.sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 8.26-8.21 (m, 1 H), 7.83
(t, 2 H), 7.56-7.37 (m, 4 H), 5.89 (d, 2 H), 4.71 (s, 2 H),
4.17-4.06 (m, 1 H), 2.84 (d, 2 H), 2.49 (t, 2 H), 2.39 (t, 2 H),
2.21-2.11 (m, 4 H), 1.93-1.82 (p, 2 H), 1.62-1.49 (m, 2 H)
.sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 173.0, 168.4, 134.1,
133.0, 129.8, 129.4, 127.7, 126.4, 125.6, 124.8, 124.2, 124.1,
73.8, 60.0, 57.0, 52.0, 46.5, 31.6, 22.0, 14.1
MS (ES): 494.2 [M+Na].sup.+
Example 8
Hydrolysis of the Trichloroethyl Ester from Example 7
##STR00035##
Following the procedure outlined in example 4, the trichloroethyl
ester from example 7 (0.67 g, 1.4 mmol) was converted to the title
compound as a white solid (0.38 g, 79.6%).
.sup.1H-NMR (200 MHz, DMSO-.sub.d6): .delta. 8.50 (d, 2 H),
8.39-8.18 (m, 1 H), 8.04-7.96 (m, 2 H), 7.62-7.50 (m, 4 H), 3.91
(br s, 1 H), 2.93 (d, 2 H), 2.37 (t, 2 H), 2.23-2.06 (m, 4 H), 1.92
(d, 2 H), 1.72-1.57 (m, 4 H)
.sup.13C-NMR (50 MHz, DMSO-.sub.d6): .delta. 167.9, 135.1, 133.0,
129.7, 129.5, 128.1, 126.6, 126.1, 125.3, 125.0, 124.9, 57.4, 52.0,
46.6, 38.6, 33.5, 31.2, 22.2
MS (ES): 363.1 [M+Na].sup.+
Example 9
Alkylation of N-(piperidin-4-yl)napth-1-yl carboxamide
hydrochloride with ethyl 4-bromobutyrate
##STR00036##
Following the procedure outlined in example 7,
N-(piperidin-4-yl)napth-1-yl carboxamide hydrochloride 6 (0.58 g,
2.0 mmol) was converted to the title compound as a white solid
(0.67 g, 91.4%).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 8.24 (d, 1 H), 7.89-7.82
(m, 2 H), 7.54-7.49 (m, 3 H), 7.40 (t, 1 H), 6.07 (d, 2 H),
4.14-4.07 (m, 3 H), 2.84 (d, 2 H), 2.36-2.28 (m, 4 H), 2.13-2.04
(m, 4 H), 1.81-1.76 (p, 2 H), 1.55-1.51 (m, 2 H), 1.26 (t, 3 H)
.sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 173.3, 168.7, 134.5,
133.4, 130.2, 129.8, 128.1, 126.8, 126.1, 125.1, 124.6, 124.5,
60.1, 57.4, 52.1, 46.9, 32.0, 22.2, 14.0
MS (ES): 391.2 [M+Na].sup.+
Example 10
Preparation of intermediate (piperidin-4-yl)ethylcarboxylate
hydrochloride
##STR00037##
To a stirred solution of isonipectoic acid (12.9 g, 0.10 mol) in
absolute ethanol (200 ml) was cooled to 0.degree. C. and SOCl.sub.2
(47.5 g, 0.40 mol) dropwise added. The mixture was stirred to room
temperature and heated to reflux for 3 h. The reaction mixture was
evaporated in vacuo and the residue dissolved in a 10% aqueous
solution of NaOH (250 ml). The aqueous solution was extracted with
CH.sub.2Cl.sub.2 (3.times.100 ml). The organic extracts was dried
over NaSO.sub.4, filtered and evaporated in vacuo. The residue was
dissolved in dry ethanol and HCl bubbled into the solution to give
the hydrochloride precipitate. The residue was recrystallized from
absolute ethanol to give the product as a white solid (17.46 g,
90.2%).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.40 (br s, 2 H),
4.09-4.02 (q, 2 H), 3.30 (d, 2 H), 3.01-2.95 (m, 2 H), 2.56-2.47
(m, 1 H), 2.14-1.95 (m, 4 H), 1.30 (t, 3 H)
Example 11
Preparation of intermediate
(1-benzylpiperidin-4-yl)ethylcarboxylate hydrochloride
##STR00038##
A suspension of (piperidin-4-yl)ethylcarboxylate hydrochloride (8.6
g, 44.4 mmol) and K.sub.2CO.sub.3 (24.5 g, 0.17 mol) in acetone
(200 ml) was added benzylbromide (9.11 g, 53.3 mmol) and heated to
reflux for 12 h. The solvent was evaporated in vacuo and the
residue added H.sub.2O (200 ml). The aqueous layer was extracted
with Et.sub.2O (3.times.100 ml) and the organic extracts dried over
Na.sub.2SO.sub.4, filtered and evaporated in vacuo. The residue was
dissolved in acetone and HCl bubbled into the solution to give the
hydrochloride precipitate. The precipitate was filtered, dried and
recrystallized from acetone to give the expected product as a white
solid (11.03 g, 87.6%).
.sup.1H-NMR (300 MHz, DMSO-.sub.d6): .delta. 11.48 (br s, 1 H),
7.67 (s, 2 H), 7.42 (s, 3 H), 4.30-4.25 (m, 2 H), 4.11-4.01 (m, 2
H), 3.28 (d, 2 H), 2.97-2.84 (m, 2 H), 2.15-1.99 (m, 4 H) 1.15 (t,
3 H)
Example 12
Preparation of intermediate 1-[(1-benzylpiperidin-4-yl)methanol
##STR00039##
A suspension of LiAlH.sub.4 (1.52 g, 40.0 mmol) in dry THF (30 ml)
was stirred at 0.degree. C. and dropwise added a solution of
1-benzylpiperidin-4-yl)ethylcarboxylate hydrochloride (2.47 g, 10.0
mmol) in dry THF (50 ml). The obtained mixture was heated under
reflux for 4 h and then cooled to room temperature. EtOAc (200 ml),
water (40 ml), and a 2 N aqueous solution of NaOH (10 ml) were
added. The obtained mineral precipitate was filtered through a pad
of kiselguhr, the filtrate evaporated in vacuo and water (50 ml)
added to the residue. The aqueous layer was extracted with
CH.sub.2Cl.sub.2 (3.times.50 ml) and the organic extracts combined
and dried over Na.sub.2SO.sub.4, filtered and evaporated in vacuo
to give the product as a colourless oil (1.75 g, 85.6%)
.sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 7.40-7.26 (m, 5 H),
3.53-3.46 (m, 4 H), 2.94 (d, 2 H), 2.61 (br s, 1 H), 2.00 (t, 2 H),
1.75 (d, 2 H), 1.48-1.26 (m, 3 H)
Example 13
Synthesis of
1-[(1-benzylpiperidin-4-yl)carboxymethyl]napthalene
##STR00040##
A stirred solution of (1-benzylpiperidin-4-yl)methanol (2.79 g,
13.7 mmol) and NEt.sub.3 (1.65 g, 16.3 mmol) in CH.sub.2Cl.sub.2
(50 ml) was cooled to 0.degree. C. and dropwise added a solution of
napthoyl chloride (prepared as in example 7) (3.11 g, 16.3 mmol)
dissolved in CH.sub.2Cl.sub.2/THF (1:1, 50 ml). The resulting
mixture was stirred to room temperature overnight, evaporated in
vacuo and the residue added EtOAc (100 ml). The organic layer
washed with water (50 ml), brine (50 ml) and water (50 ml). The
organic layer was dried over Na.sub.2SO.sub.4, filtered and
evaporated in vacuo to give an oil. The oil was separated with
flash chromatography (SiO.sub.2, EtOAc) to give the expected
product as a yellow oil (3.12 g, 63.3
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 8.94 (d, 1 H), 8.22-8.19
(m, 1 H), 8.04 (d, 1 H), 7.90 (d, 1 H), 7.64-7.49 (m, 3 H),
7.49-7.25 (m, 5 H), 4.30 (d, 2 H), 3.52 (s, 2 H), 2.98 (d, 2 H),
2.09-2.00 (m, 2 H), 1.93-1.83 (m, 3 H), 1.57-1.45 (m, 2 H)
MS (ES): 360.1 [M+H].sup.+
Example 14
Preparation of intermediate
1-[(piperidin-4-yl)methyloxycarbonyl]napthalene hydrochloride
##STR00041##
Following the procedure outlined in Example 6,
1-[(1-benzylpiperidin-4-yl)carboxymethyl]napthalene (1.69 g, 4.70
mmol) was converted to the title compound as a yellow solid (1.07
g, 74.5%).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.60 (br s, 2 H), 8.86
(d, 1 H), 8.17 (d, 1 H), 8.00 (d, 1 H), 7.85 (d, 1 H), 7.61-7.34
(m, 3 H), 4.28 (d, 2 H), 3.55 (d, 2 H), 2.89 (d, 2 H), 2.04-1.68
(m, 5 H)
Example 15
Alkylation of 1-[(piperidin-4-yl)methyloxycarbonyl]napthalene
hydrochloride with 2,2,2-trichloroethyl 4-bromobutyrate
##STR00042##
Following the procedure outlined in Example 7,
1-[(piperidin-4-yl)methyloxycarbonyl]napthalene hydrochloride (0.30
g, 1.0 mmol) was converted to the title compound as a white solid
(0.43 g, 89.5%).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 8.89 (d, 1 H), 8.18-8.14
(m, 1 H), 8.00 (d, 1 H), 7.88-7.84 (m, 1 H), 7.63-7.43 (m, 3 H),
4.72 (s, 2 H), 4.24 (d, 2 H), 2.93 (d, 2 H), 2.49 (t, 2 H), 2.38
(t, 2 H), 1.96-1.79 (m, 8 H), 1.46-1.27 (m, 2 H)
.sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 171.9, 167.5, 133.8,
133.2, 131.3, 130.0, 128.5, 127.7, 127.2, 126.1, 125.7, 124.4,
95.0, 73.9, 69.3, 60.3, 57.7, 53.3, 35.5, 31.9, 29.1, 22.1, 21.0,
14.1
MS (ES): 487.1 [M+H].sup.+
Example 16
Alkylation of 1-[(piperidin-4-yl)methyloxycarbonyl]napthalene
hydrochloride with ethyl 4-bromobutyrate
##STR00043##
Following the procedure outlined in example 7,
1-[(piperidin-4-yl)methyloxycarbonyl]napthalene hydrochloride (0.39
g, 1.27 mmol) was converted to the title compound as a yellow oil.
The oil was dissolved in Et.sub.2O and HCl bubbled into the
solution to give the hydrochloride precipitate. The precipitate was
filtered off, dried and recrystallized from acetonitrile to leave
the hydrochloride salt (0.31 g, 73.8%).
.sup.1H-NMR (300 MHz, DMSO-.sub.d6): .delta. 10.7 (br s, 1 H), 8.76
(d, 1 H), 8.23 (t, 2 H), 8.04 (d, 1 H), 7.71-7.59 (m, 3 H), 4.28
(d, 2 H), 4.11-4.03 (q, 2 H), 3.49 (d, 2 H), 3.51-2.96 (m, 5 H),
2.41 (t, 2 H), 2.00-1.83 (m, 7 H), 1.19 (t, 3 H)
.sup.13C-NMR (75 MHz, DMSO-.sub.d6): .delta. 172.8, 167.4, 134.4,
134.2, 131.3, 131.0, 129.6, 128.8, 127.3, 127.2, 125.8, 125.7,
68.6, 60.9, 56.0, 52.0, 33.7, 31.4, 26.4, 19.6, 14.9
MS (ES): 406.2 [M+Na].sup.+
Example 17
Hydrolysis of the Trichloroethyl Ester from Example 16
##STR00044##
Following the procedure outlined in example 4, the trichloroethyl
ester from example 16 (0.43 g, 0.88 mmol) was converted to the
title compound as a white solid (0.25 g, 79.9
.sup.1H-NMR (300 MHz, DMSO-.sub.d6): .delta. 10.11, 8.75 (d, 1 H),
8.15 (t, 2 H), 8.01 (d, 1 H), 7.68-7.57 (m, 3 H), 4.20 (d, 2 H),
2.90 (d, 2 H), 2.33 (t, 2 H), 2.20 (t, 2 H), 2.03-1.92 (t, 2 H),
1.75-1.60 (m, 5 H), 1.45-1.30 (m, 2 H)
.sup.13C-NMR (75 MHz, DMSO-.sub.d6): .delta. 175.0, 166.6, 133.4,
133.3, 130.4, 129.8, 128.6, 127.8, 126.7, 126.3, 125.0, 124.8,
68.7, 57.4, 52.3, 34.7, 33.2, 28.0, 21.6
MS (ES): 378.1 [M+Na].sup.+
Example 18
Alkylation of 1-[(piperidin-4-yl)methyloxycarbonyl]napthalene
hydrochloride with diethyl 2-bromoethylphosphonate
##STR00045##
Following the procedure outlined in example 7, 1-[(piperidin-4
yl)methyloxycarbonyl]-napthalene hydrochloride (0.63 g, 2.06 mmol)
was converted to the title compound as a yellow oil. The oil was
dissolved in Et.sub.2O and HCl bubbled into the solution to give a
white precipitate. The precipitate was filtered off, dried and
recrystallized from acetonitrile to leave the hydrochloride salt
(0.37 g, 37.9%)
.sup.1H-NMR (300 MHz, DMSO-.sub.d6): .delta. 11.0 (br s, 1 H), 8.78
(d, 1 H), 8.28-8.21 (m, 2 H), 8.09-8.05 (m, 1H), 4.30 (d, 2 H),
4.14-4.03 (q, 4 H), 3.63-3.52 (m, 2 H), 3.20-2.95 (m, 5 H),
2.48-2.37 (m, 1 H), 2.02-1.81 (m, 5 H), 1.28 (t, 6 H)
.sup.13C-NMR (75 MHz, DMSO-.sub.d6): .delta. 166.5, 133.4, 133.3,
130.4, 130.1, 128.7, 127.9, 126.4, 126.3, 124.9, 124.8, 67.7, 61.6,
61.5, 50.7, 50.0, 32.9, 26.5, 21.1, 19.3, 16.2, 16.1
MS (ES): 456.2 [M+N].sup.+
Example 19
Preparation of intermediate
N-(1-benzylpiperidin-4-yl)-indazole-3-carboxamide
##STR00046##
A stirred solution of 1-H-indazole-3-carboxylic acid (8.11 g, 50.0
mmol) in dry DMF (140 ml) under argon atmosphere was added CDI
(8.92 g, 55 mmol) and heated at 60.degree. C. for 2 h. The mixture
was cooled to room temperature, dropwise added
4-amino-1-benzylpiperidine (9.51 g, 50.0 mmol) previously dissolved
in DMF (20 ml). The mixture was heated at 60.degree. C. for 2 h,
cooled to room temperature and the solvent evaporated in vacuo. The
residue was added CH.sub.2Cl.sub.2 (250 ml) and the organic layer
washed with H.sub.2O (100 ml), 1 N aqueous NaOH (100 ml), H.sub.2O
(100 ml) and brine (100 ml). The organic layer was dried over
Na.sub.2SO.sub.4, filtered and evaporated in vacuo. The residue was
recrystalilized from EtOH to leave the expected product as a white
solid (14.23 g, 85.1%).
.sup.1H-NMR (200 MHz, DMSO-.sub.d6): .delta. 13.59, 8.20 (t, 2 H),
7.61 (t, 1 H), 7.38-7.21 (m, 7 H), 3.95-3.87 (m, 1 H), 3.49 (s, 2
H), 2.80 (d, 2 H), 2.04 (t, 2 H), 1.78-1.67 (4 H)
Example 20
Preparation of intermediate
N-(1-benzylpiperidin-4-yl)-1-isopropylindazole-3-carboxamide
##STR00047##
A solution of N-(1-benzylpiperidin-4-yl)-indazole-3-carboxamide
(3.34 g, 10.0 mmol) in dry DMF (70 ml) under argon atmosphere was
added sodium hydride (0.25 g, 10.0 mmol) and stirred at room
temperature for 3 h. The mixture was added isopropylbromide (1.37
g, 11.0 mmol) and stirred for additional 24 h. The reaction mixture
was evaporated in vacuo and the residue added EtOAc (100 ml). The
organic layer washed with brine (50 ml) and H.sub.2O (2.times.50
ml). The organic layer was dried over Na.sub.2SO.sub.4, filtered
and evaporated in vacuo to leave an oil that solidified upon
standing. The oil was separated with flash chromatography
(SiO.sub.2, Et.sub.2O/Hexane (2:1) to leave the product as a solid
(1.22 g, 32.7%).
.sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 8.40 (d, 1 H), 7.44-7.27
(m, 8 H), 6.95 (d, 1 H), 4.92-4.83 (p, 1 H), 4.05-3.95 (m, 1 H),
3.55 (s, 1 H), 2.91 (d, 2 H), 2.21 (t, 2 H), 2.08 (d, 2 H),
1.71-1.60 (m, 8 H)
Example 21
Preparation of intermediate
N-(1-piperidin-4-yl)-1-isopropylindazole-3-carboxamide
hydrochloride
##STR00048##
Following the procedure outlined in Example 6,
N-(1-benzylpiperidin-4-yl)-1-isopropylindazole-3-carboxamide (1.77
g, 4.28 mmol) was converted to the title compound as a white solid
(1.26 g, 91.1%).
.sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 9.80 (br s, 1 H), 9.68
(br s, 1 H), 8.34 (d, 1 H), 7.49-7.31 (m, 2 H), 7.28-7.26 (m, 1 H),
7.05 (d, 1 H), 4.94-4.85 (m, 1 H), 4.35-4.32 (m, 1 H), 3.62 (d, 2
H), 3.15-3.04 (m, 2 H), 2.36-2.32 (m, 2 H), 2.18-2.08 (m, 3 H),
1.65 (d, 6 H)
Example 22
Alkylation of
N-(1-piperidin-4-yl)-1-isopropylindazole-3-carboxamide
hydrochloride with ethyl 4-bromobutyrate
##STR00049##
Following the procedure outlined in Example 7,
N-(1-piperidin-4-yl)-1-isopropylindazole-3-carboxamide
hydrochloride (0.32 g, 1.0 mmol) was converted to the title
compound as a colourless oil (0.37 g, 93.7%).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 8.38 (d, 1 H), 7.43-7.37
(m, 3 H), 7.26 (d, 1 H), 4.90-4.82 (m, 1 H), 4.19-4.08 (m, 1 H),
2.91 (d, 2 H), 2.43-2.31 (m, 4 H), 2.19-2.03 (m, 5 H), 1.87-1.58
(m, 11 H), 1.26 (t, 3 H)
.sup.13C-NMR (75 MHz, CDCl.sub.3): .delta.173.3, 162.0, 139.8,
136.7, 126.2, 122.8, 122.7, 122.2, 109.1, 60.1, 57.4, 52.3, 50.7,
46.0, 32.2, 32.1, 22.2, 21.9, 14.1
MS (ES): 423.1 [M+Na.sup.+]
Conversion to the hydrochloride salt was effected using ethereal
HCl.
Example 23
Alkylation of
N-(1-piperidin-4-yl)-1-isopropylindazole-3-carboxamide
hydrochloride with 2,2,2-trichloroethyl 4-bromobutyrate
##STR00050##
A stirred suspension of
N-(1-piperidin-4-yl)-1-isopropylindazole-3-carboxamide
hydrochloride (0.32 g, 1.0 mmol) and K.sub.2CO.sub.3 (0.55 g, 4.0
mmol) in acetone (15 ml) was added 2,2,2-trichloroethyl
4-bromobutyrate (0.45 g, 1.5 mmol) and heated under reflux for 12
h. The mixture was cooled to room temperature, filtered and the
filtrate evaporated in vacuo. The residue was added EtOAc (30 ml)
and the organic layer washed with H.sub.2O (15 ml), brine (15 ml)
and H.sub.2O (15 ml). The organic layer was dried over
Na.sub.2SO.sub.4, filtered and the solvent evaporated in vacuo to
leave an oil. The oil was dissolved in acetone and dropwise added
1.0 M HCl in Et.sub.2O to give a white precipitate. The precipitate
was filtered off, dried and recrystallized from acetone to leave
the hydrochloride salt as a white powder (0.47 g, 87.0%).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 12.44 (br s, 1 H), 8.29
(d, 1 H), 7.47-7.37 (m, 2 H), 7.25 (t, 1 H), 7.16 (d, 1 H),
4.89-4.85 (m, 1 H), 4.76 (s, 2 H), 4.19-4.08 (m, 1 H), 3.71 (d,
2H), 3.14-2.69 (m, 4 H), 2.34-2.03 (m, 8 H), 1.61 (d, 6 H)
.sup.13C-NMR (75 MHz, CDCl.sub.3): .delta.170.3, 162.4, 139.9,
135.9, 126.4, 122.8, 122.6, 122.3, 109.3, 94.6, 74.0, 56.2, 52.2,
50.9, 43.8, 30.7, 29.1, 22.0, 18.9, 15.2
MS (ES): 526.2 [M+Na].sup.+
Example 24
Hydrolysis of the Trichloroethyl Ester from Example 23
##STR00051##
Following the example outlined in example 4, the trichloroethyl
ester from example 23 (0.37 g, 0.69 mmol) was converted to the
title compound as a white solid (0.20 g, 77.9
.sup.1H-NMR (300 MHz, CD.sub.3OD): .delta. 8.21 (d, 1 H), 7.61 (d,
1 H), 7.42-7.37 (m, 1 H), 7.24 (t, 1 H), 5.01-4.93 (m, 1 H),
4.24-4.19 (m, 1 H), 3.51 (d, 2 H), 3.05-2.91 (m, 4 H), 2.45 (t, 2
H), 2.18-2.14 (m, 2 H), 1.99-1.88 (m, 4 H), 1.57 (d, 6 H)
.sup.13C-NMR (75 MHz, CD.sub.3OD): .delta. 181.1, 164.5, 141.4,
137.6, 127.6, 124.0, 123.7, 123.0, 110.9, 59.1, 52.6, 52.1, 45.6,
37.4, 30.5, 22.3, 21.7
MS (ES): 395.1 [M+Na].sup.+
Example 25
Preparation of intermediate 4-bromomethyl benzoic acid
2,2,2-trichloroethyl ester
##STR00052##
A solution of 2,2,2-trichloroethanol (2.46 g, 16.5 mmol) and
NEt.sub.3 (1.67 g, 16.5 mmol) in CH.sub.2Cl.sub.2 (40 ml) at
0.degree. C. was dropwise added 4-bromomethyl benzoylbromide (4.17
g, 15.0 mmol) in CH.sub.2Cl.sub.2 (20 ml) and stirred to room
temperature overnight. The reaction mixture was added H.sub.2O (20
ml) and the organic layer separated. The organic layer washed with
aqueous 1 M HCl (20 ml) and H.sub.2O (20 ml). The organic layer was
dried over Na.sub.2SO.sub.4, filtered and the solvent evaporated in
vacuo to leave the expected product as a white solid. The product
was used directly in the next step without any further purification
(to be filled in).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 7.86 (dd, 4 H), 5.00 (s,
2 H), 4.54 (s, 2 H)
Example 26
Alkylation of
N-(1-piperidin-4-yl)-1-isopropylindazole-3-carboxamide
hydrochloride with 4-bromomethyl benzoic acid 2,2,2-trichloroethyl
ester
##STR00053##
Following the procedure outlined in Example 7,
N-(1-piperidin-4-yl)-1-isopropylindazole-3-carboxamide
hydrochloride (0.41 g, 1.3 mmol) was converted to the title
compound as a colourless oil (0.61 g, 85.2%).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 8.38 (d, 1 H), 8.09 (d,
2 H), 7.50-7.36 (m, 4 H), 7.29-7.23 (m, 1 H), 6.95 (d, 1 H) 4.98
(s, 2 H), 4.92-4.83 (p, 1 H), 4.13-4.04 (m, 1 H), 3.60 (s, 2 H),
2.88 (d, 2 H), 2.24 (t, 2 H), 2.10-2.05 (m, 2 H), 1.75-1.61 (m, 8
H),
.sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 165.2, 162.6, 145.9,
140.3, 137.3, 130.5, 129.3, 128.1, 127.8, 126.7, 123.4, 123.3,
122.8, 109.8, 95.6, 74.7, 63.0, 53.0, 51.3, 46.4, 32.8, 22.5
MS (ES): 551.1 [M+H].sup.+
Example 27
Hydrolysis of the Trichloroethyl Ester from Example 26
##STR00054##
Following the procedure outlined in Example 4, the trichloroethyl
ester from example 26 (0.42 g, 0.76 mmol) was converted to the
title compound as a white solid (0.25 g, 78.9
.sup.1H-NMR (300 MHz, CD.sub.3OD): .delta. 8.22 (d, 1 H), 8.04 (d,
1 H), 7.66 (d, 1 H), 7.48-7.41 (m, 3 H), 7.26 (t, 1 H), 5.08-4.99
(m, 1 H), 4.10-4.03 (m, 1H), 3.13 (d, 2 H), 2.53 (t, 2 H),
2.08-2.04 (m, 2 H), 1.92-1.85 (m, 2 H), 1.61 (d, 2 H)
.sup.1H-NMR (75 MHz, CD.sub.3OD): .delta. 163.5, 140.4, 136.7,
129.7, 126.6, 123.0, 122.6, 122.0, 109.9, 61.7, 52.2, 51.1, 46.0,
30.6, 21.3
MS (ES): 419.1 [M+H].sup.+
Example 28
Preparation of intermediate
4-aminomethyl-1-(tert-butoxycarbonyl)piperidine
##STR00055##
Benzaldehyde (8.73 g, 82.3 mmol) was added all at once to a stirred
solution of 4-aminomethylpiperidine (9.42 g, 82.3 mmol) in toluene
(100 ml). The mixture was heated under reflux for 4 h with a
Dean-Stark trap attached to collect the water. The reaction mixture
was cooled to room temperature and di-tert-butyldicarbonate (19.75
g, 90.5 mmol) was added in divided portions under continuously
stirring. The mixture was stirred overnight, evaporated in vacuo
and the residue stirred vigorously with aqueous 1 N KHSO.sub.4 (100
ml) at room temperature for 4 h. The mixture was extracted with
Et.sub.2O (3.times.100 ml) and then the aqueous layer was made
strongly basic with NaOH. The aqueous layer was extracted with
CH.sub.2Cl.sub.2 (3.times.100 ml). The combined extracts were dried
with Na.sub.2SO.sub.4, filtered and the solvent evaporated in vacuo
to leave the product as an oil (15.4 g, 86.5%).
.sup.1H-NMR (200 MHz, DMSO-.sub.d6): .delta. 4.04-4.01 (m, 2 H),
2.60 (t, 2 H), 2.50 (d, 2 H), 1.62 (d, 2 H), 1.32 (s, 9 H),
1.31-1.28 (m, 1 H), 1.06 (br s, 2 H), 1.03-0.93 (m, 2 H)
Example 29
Synthesis of
4-amino-N-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-5-chloro-2-methoxybe-
nzamide
##STR00056##
A mixture of 4-aminomethyl-1-(tert-butoxycarbonyl)piperidine (10.0
g, 46.7 mmol), 4-amino-5-chloro-2-methoxybenzoic acid (9.41 g, 46.7
mmol) and NEt.sub.3 (6.80 ml, 46.7 mmol) in DMF (100 ml) were added
1-ethyl-3-[3-(dimethylamino)propyl]carbodiimide hydrochloride (EDC)
(9.39 g, 46.7 mmol) and 1-hydroxybenzotriazole (HOBT) (6.62 g, 46.7
mmol) at 0.degree. C. The reaction mixture was stirred to room
temperature overnight and concentrated in vacuo. The resulting
residue was added H.sub.2O (100 ml) and extracted with EtOAc. The
combined organic extracts were washed with aqueous K.sub.2CO.sub.3
and dried over Na.sub.2SO.sub.4. The solvent was removed in vacuo
and the residue separated with flash chromatography (SiO.sub.2,
EtOAc) to give the expected product as a white solid (11.91 g,
64.1%).
.sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 8.06 (s, 1 H), 7.77 (t,
1 H), 6.33 (s, 1 H), 4.64 (s, 2 H), 4.08 (d, 2 H), 3.86 (s, 3 H),
3.30 (t, 2 H), 2.67 (t, 2 H), 1.78-1.66 (m, 3 H), 1.43 (s, 9 H),
1.24-1.11 (m, 2 H)
Example 30
Preparation of intermediate
4-amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide
hydrochloride
##STR00057##
A stirred solution of
4-amino-N-(tert-butoxycarbonyl)piperidin-4-ylmethyl]-5-chloro-2-methoxybe-
nzamide (1.70 g, 4.3 mmol) in 1,4-dioxane (30 ml) at 0.degree. C.
was added 4 M HCl in 1,4-dioxane (10 ml) in portions. The reaction
mixture was stirred to room temperature for 4 h, evaporated in
vacuo and the residue recrystallized from acetone to leave the
product as a red solid (0.89 g, 61.8%).
.sup.1H-NMR (300 MHz, DMSO-.sub.d6): .delta. 9.28 (br s, 1 H), 9.04
(br s, 1 H), 8.00 (t, 1 H), 7.64 (s, 1 H), 7.31 (br s, 4 H), 6.58
(s, 1 H), 3.81 (s, 3 H), 3.21-3.16 (m, 4 H), 2.82-2.71 (q, 2 H),
1.80-1.71 (m, 3 H), 1.45-0.34 (m, 2 H)
Example 31
Alkylation of
4-amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide
hydrochloride with ethyl 4-bromobutyrate
##STR00058##
Following the method outlined in Example 7,
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide
hydrochloride (0.76 g, 1.98 mmol) was converted to the title
compound as an oil (0.57 g, 69.9%).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 8.08 (s, 1 H), 7.74 (t,
1 H), 6.30 (s, 1 H), 4.49 (s, 2 H), 4.14-4.07 (q, 2 H), 3.87 (s, 3
H), 3.30 (t, 2 H), 2.90 (d, 2 H), 2.35-2.28 (m, 4 H), 1.94-1.69 (m,
7 H), 1.29-1.18 (m, 5 H)
.sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 173.9, 164.9, 157.7,
147.0, 133.4, 112.9, 111.9, 98.2, 66.2, 58.3, 56.5, 53.8, 45.5,
36.5, 32.7, 30.4, 15.6
MS (ES): 411.9 [M+H].sup.+
Conversion to the hydrochloride salt was effected with ethereal
HCl.
Example 32
Alkylation of
4-amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide
hydrochloride with diethyl 2-bromoethylphosphonate
##STR00059##
Following the procedure outlined in Example 7,
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide
hydrochloride (1.53 g, 4.0 mmol) was converted to the title
compound as an oil (1.12 g, 57.1%).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 7.99 (s, 1 H), 7.70 (t,
1 H), 6.29 (s, 1 H), 4.66 (s, 2 H), 4.08-3.97 (m, 4 H), 3.80 (s, 3
H), 3.24 (t, 2 H), 2.83 (d, 2 H), 2.58-2.53 (m, 2 H), 1.96-1.84 (m,
4 H), 1.66 (d, 2 H), 1.55-1.47 (m, 1 H), 1.30-1.22 (m, 8 H)
.sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 165.0, 157.7, 147.6,
133.1, 112.3, 111.6, 98.1, 61.9, 56.4, 53.2, 52.0, 45.3, 36.4,
29.5, 24.9, 23.1, 16.8
MS 462.1 [M+H].sup.+
Conversion to the hydrochloride salt was effected using ethereal
HCl.
Example 33
Preparation of intermediate 1-benzyl-4-carbonylamide piperidine
##STR00060##
A stirred suspension of isonipectamide (16.5 g, 0.13 mol) and
K.sub.2CO.sub.3 (35.6 g, 0.26 mol) in EtOH (350 ml) was added
benzylbromide (22.0 g, 0.13 mol) and heated under reflux for 3 h,
cooled to room temperature and filtered. The filtrate was
evaporated in vacuo and added H.sub.2O (200 ml). The aqueous layer
was extracted with CH.sub.2Cl.sub.2 (3.times.150 ml), the organic
layers combined and dried over Na.sub.2SO.sub.4 and filtered. The
solvent was evaporated in vacuo to leave the product as a white
solid (20.0 g, 71.0%).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 7.34-7.21 (m, 5 H), 6.36
(br s, 1 H), 5.80 (br s, 1 H), 3.49 (s, 2 H), 2.92 (d, 2 H),
2.14-1.99 (m, 1 H), 1.96 (t, 2 H), 1.85-1.72 (m, 4 H)
Example 34
Preparation of intermediate 1-benzyl-4-cyano-piperidine
##STR00061##
1-Benzyl-4-carbonylamide piperidine (20.0 g, 91.7 mmol) was mixed
with P.sub.2O.sub.5 (16.92, 119.2 mmol) and heated under argon at
180-200.degree. C. for 3 h, cooled to room temperature and added
H.sub.2O (150 ml). The aqueous solution was basified by careful
addition of K.sub.2CO.sub.3 and then extracted with EtOAc
(3.times.150 ml). The organic extracts were dried over
Na.sub.2SO.sub.4, filtered and the solvent evaporated in vacuo to
leave a yellow oil (16.7 g, 90.9%).
.sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 7.41-7.25 (m, 5 H), 3.53
(s, 2 H), 2.75-2.64 (m, 2 H), 2.40-2.34 (m, 2 H), 1.98-1.86 (m, 5
H)
Example 35
Preparation of intermediate 1-benzyl-4-aminomethylpiperidine
##STR00062##
A suspension of LiAlH.sub.4 (4.84 g, 0.128 mol) in dry Et.sub.2O
(40 ml) under argon atmosphere at 0.degree. C. was dropwise added a
solution of 1-benzyl-4-cyano-piperidine (18.3 g, 91.5 mmol) in dry
Et.sub.2O (80 ml) and stirred to room temperature for 24 h. The
reaction mixture was treated carefully with H.sub.2O (10 ml), 10%
aqueous NaOH (10 ml) and H.sub.2O (30 ml) to give a mineral
precipitate. The precipitate was filtered through a pad of
kiselguhr, washed with Et.sub.2O and the filtrate evaporated in
vacuo to leave the product as an oil (21.4 g, 82.3%).
.sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 7.37-7.22 (m, 5 H), 6.42
(br s, 1 H), 5.84 (br s, 1 H), 3.51 (s, 2 H), 2.94 (d, 2 H),
2.16-1.67 (m, 7 H)
Example 36
Preparation of intermediate methyl
2-(3-chloropropoxy)indole-3-carboxylate
##STR00063##
A suspension of methyl indole-3-carboxylate (5.25 g, 30.0 mmol) and
DABCO (1.84 g, 16.4 mmol) in dry CH.sub.2Cl.sub.2 (25 ml) was
cooled to 0.degree. C. under argon atmosphere, treated in one
portion with NCS (4.41 g, 33.0 mmol) and the mixture stirred for 10
min. The resulting solution was added to a solution of
3-chloropropan-1-ol (3.12 g, 33.0 mmol) in dry CH.sub.2Cl.sub.2 (25
ml) containing anhydrous methane sulphonic acid (0.23 ml). The
resulting suspension was stirred for 30 min and then washed with
10% aqueous Na.sub.2CO.sub.3 solution (3.times.25 ml). The organic
layer was dried over Na.sub.2SO.sub.4, filtered and concentrated in
vacuo. The resulting oil was triturated with toluene (10 ml) at
0.degree. C. for 1 h and the solid precipitate filtered, washed
with a small amount of toluene and dried in vacuo to leave the
product as an off-white solid (5.22 g, 65.0%).
.sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 9.51 (s, 1 H), 8.04 (d,
1 H), 7.28-7.14 (m, 3 H), 4.49 (t, 2 H), 3.96 (s, 3 H), 3.67 (t, 2
H), 2.18-2.10 (m, 2 H)
Example 37
Preparation of intermediate methyl
3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxylate
##STR00064##
Methyl 2-(3-chloropropoxy)indole-3-carboxylate (5.0 g, 18.7 mmol)
was added to a stirred mixture of 5.4 M aqueous M NaOH (3.8 ml) and
toluene (50 ml) and heated at 40.degree. C. for 4 h. The aqueous
layer was separated and the organic layer washed with H.sub.2O
(3.times.25 ml) while maintaining the temperature at 60.degree. C.
The organic solvent was evaporated in vacuo to leave the product as
a white solid (4.0 g, 93.2%).
.sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 8.0 (dd, 1 H), 7.24-7.12
(m, 3 H), 4.50 (t, 2 H), 4.06 (t, 2 H), 3.91 (s, 3 H), 2.34-2.26
(m, 2 H)
Example 38
Preparation of intermediate
3,4-dihydro-N-[1-(phenylmethoxy)-4-piperidinyl]methyl]-2H-[1,3]oxazino[3,-
2-a]indole-10-carboxamide
##STR00065##
Trimethylaluminium (2 M in toluene, 9 ml) was diluted with dry
toluene (9 ml) and the solution cooled to 0.degree. C. under argon
atmosphere. 1-Benzyl-4-aminomethylpiperidine (from example 37)
(3.37 g, 16.5 mmol) was added to the solution, followed by methyl
3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxylate (from
example 39) (3.81 g, 16.5 mmol). The reaction mixture was heated
under reflux for 5 h, cooled to room temperature and 10% aqueous
NaOH solution (40 ml) dropwise added. The toluene layer washed with
H.sub.2O, brine and evaporated in vacuo to give an oil. The residue
was purified by flash chromatography (SiO.sub.2,
CH.sub.2Cl.sub.2/MeOH (7:3)) to leave the product as an off white
solid (3.52 g, 53.4%).
.sup.1H-NMR (300 MHz, DMSO-d.sub.6): .delta. 8.34 (d, 1 H),
7.33-7.06 (m, 8 H), 6.53 (t, 1 H), 4.49 (t, 2 H), 4.04 (t, 2 H),
3.51 (s, 3 H), 3.34 (t, 2 H), 2.92 (d, 2 H), 2.36-2.28 (q, 2 H),
2.03-1.95 (m, 2 H), 1.78-1.62 (m, 3 H), 1.43-1.34 (m, 2 H)
Example 39
Preparation of intermediate
3,4-dihydro-N-[4-piperidinyl]methyl]-2H-[1,3]oxazino[3,2-a]indole-10-carb-
oxamide
##STR00066##
A stirred solution of
3,4-dihydro-N-[1-(benzyl)-4-piperidinyl]methyl]-2H-[1,3]oxazino[3,2-a]ind-
ole-10-carboxamide (2.01 g, 5.0 mol) in EtOH (20 ml) was added
hydrazine monohydrate (0.36 ml) and 10% palladium on activated
charcoal (M-type, 0.40 g) and heated under reflux for 2 h. The
reaction mixture was cooled to room temperature, filtered through a
pad of kiselguhr and the filtrate evaporated in vacuo to leave the
expected product as a white solid (1.52 g, 97.3%).
.sup.1H-NMR (200 MHz, DMSO-.sub.d6): .delta. 8.09-8.05 (m, 1 H),
7.31-7.27 (m, 1 H), 7.14-7.03 (m, 2 H), 6.81 (t, 1 H), 4.59 (t, 1
H), 4.23-4.17 (m, 1 H), 4.11 (t, 2 H), 3.17 (t, 2 H), 3.0 (d, 2 H),
2.56-2.45 (m, 2 H), 2.35-2.24 (m, 2 H), 1.66-1.61 (m, 3 H),
1.23-1.04 (m, 2 H)
Example 40
Alkylation of
3,4-dihydro-N-[4-piperidinyl]methyl]-2H-[1,3]oxazino[3,2-a]indole-10-carb-
oxamide with ethyl 4-bromobutyrate
##STR00067##
Following the procedure outlined in Example 7,
3,4-dihydro-N-[4-piperidinyl]methyl]-2H-[1,3]oxazino[3,2-a]indole-10-carb-
oxamide (0.62 g, 2.0 mmol) was converted to the title compound as a
colourless oil that crystallized upon standing (0.74 g, 86.5%).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 8.33 (d, 1 H), 7.25-7.10
(m, 3 H), 6.56 (t, 1 H), 4.55 (t, 2 H), 4.14-4.10 (m, 4 H), 3.34
(t, 2 H), 2.98 (d, 2 H), 2.43-2.31 (m, 6 H), 2.01 (t, 2 H),
1.91-1.81 (m, 4 H), 1.73-1.66 (m, 1 H), 1.42-1.37 (m, 2 H), 1.26
(t, 3 H)
.sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 173.4, 164.8, 149.2,
131.0, 125.6, 122.1, 121.0, 120.6, 107.4, 89.2, 66.8, 60.2, 57.8,
53.4, 44.2, 38.9, 36.1, 32.2, 29.7, 22.0, 21.2, 14.2
MS (ES): 450.1 [M+Na].sup.+
Conversion to the HCl-salt was effected with etheral HCl. The
precipitate was collected and recrystallized from acetone to leave
the HCl-salt as a white crystalline solid.
Example 41
Alkylation of
3,4-dihydro-N-[4-piperidinyl]methyl]-2H-[1,3]oxazino[3,2-a]indole-10-carb-
oxamide with methyl 6-bromohexanoate
##STR00068##
Following the procedure outlined in Example 7,
3,4-dihydro-N-[4-piperidinyl]methyl]-2H-[1,3]oxazino[3,2-a]indole-10-carb-
oxamide (0.31 g, 1.0 mmol) was converted to the title compound as a
white solid (0.37 g, 84.5%).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 8.33 (d, 1 H), 7.23-7.09
(m, 3 H), 6.56 (t, 1 H), 4.54 (t, 2 H), 4.10 (t, 2 H), 3.67 (s, 3
H), 3.34 (t, 2 H), 2.97 (d, 2 H), 2.38-2.29 (m, 6 H), 1.96 (t, 2
H), 1.79 (d, 2 H), 1.70-1.30 (m, 10 H)
.sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 174.1, 164.7, 149.1,
131.0, 125.5, 122.0, 121.0, 120.6, 107.4, 89.1, 66.8, 58.7, 53.5,
51.4, 44.3, 38.9, 36.2, 33.9, 29.8, 27.1, 26.4, 24.7, 21.2,
MS (ES): 464.2 [M+Na].sup.+
Example 42
Alkylation of
3,4-dihydro-N-[4-piperidinyl]methyl]-2H-[1,3]oxazino[3,2-a]indole-10-carb-
oxamide with 2,2,2-trichloroethyl 4-bromobutyrate
##STR00069##
Following the procedure outlined in Example 7,
3,4-dihydro-N-[4-piperidinyl]methyl]-2H-[1,3]oxazino[3,2-a]indole-10-carb-
oxamide (0.31 g, 1.0 mmol) was converted to the title compound as a
white solid (0.40 g, 75.8%).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 8.32 (d, 1 H), 7.27-7.14
(m, 3 H), 6.63 (t, 1 H), 4.77 (s, 2 H), 4.59 (t, 2 H), 4.15 (t, 2
H), 3.38 (t, 2 H), 3.22 (d, 2 H), 2.70 (t, 2 H), 2.59 (t, 2 H),
2.40-2.10 (m, 4 H), 2.05-1.96 (m, 2 H), 1.91-1.85 (m, 3 H),
1.77-1.60 (m, 2 H)
.sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 171.7, 166.4, 149.8,
131.5, 125.9, 122.6, 121.2, 121.1, 107.9, 95.2, 89.4, 74.3, 67.3,
57.4, 53.4, 44.2, 39.4, 35.5, 31.8, 28.8, 21.6, 21.1
MS (ES): 553.2 [M+Na].sup.+
Example 43
Hydrolysis of the Ethyl Ester from Example 40
##STR00070##
The ethyl ester from example 40 (0.51 g, 1.20 mmol) was added to a
mixture of 2 M aqueous NaOH solution (1.2 ml) and MeOH (5 ml) and
refluxed for 2 h. The reaction mixture was cooled to room
temperature, concentrated in vacuo and dropwise added 10% aqueous
HCl to pH 2. The precipitate was filtered off, washed with water
and dried in vacuo to a white crystalline solid (0.31 g,
72.9%).
.sup.1H-NMR (300 MHz, DMSO-.sub.d6): .delta. 12.31 (br s, 1 H),
10.25 (br s, 1 H), 8.10-8.04 (m, 1 H), 7.32-7.26 (m, 1 H),
7.14-7.04 (m, 2 H), 6.96 (t, 1 H), 4.59 (t, 2 H), 4.15 (t, 2 H),
3.43-3.01 (m, 8 H), 2.38-2.28 (m, 4 H), 1.97-1.81 (m, 5 H),
1.68-1.55 (m, 2 H)
.sup.13C-NMR (75 MHz, DMSO-.sub.d6): .delta. 174.3, 164.6, 150.6,
131.8, 126.1, 122.0, 120.7, 120.4, 109.3, 88.7, 67.9, 56.1, 52.4,
43.7, 34.9, 31.5, 27.7, 21.4, 19.7
MS (ES): 398.1 [M+H].sup.+
Example 44
Alkylation of
3,4-dihydro-N-[4-piperidinyl]methyl]-2H-[1,3]oxazino[3,2-a]indole-10-carb-
oxamide with diethyl 2-bromoethylphosphonate
##STR00071##
Following the procedure outlined in Example 7,
3,4-dihydro-N-[4-piperidinyl]methyl]-2H-[1,3]oxazino[3,2-a]indole-10-carb-
oxamide (0.29 g, 0.92 mmol) was converted to the title compound as
a white solid (0.36 g, 82.9%).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 8.30 (d, 1 H), 7.23-7.10
(m, 3 H), 6.59 (t, 1 H), 4.56 (t, 2 H), 4.17-4.06 (m, 6 H), 3.35
(t, 2 H), 3.09 (d, 2 H), 2.86-2.78 (q, 2 H), 2.39-2.33 (m, 2 H),
2.27-2.08 (m, 4 H), 1.88-1.60 (m, 3 H), 1.58-1.50 (m, 2 H), 1.33
(t, 6 H)
.sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 163.5, 149.8, 131.5,
125.9, 122.5, 121.3, 121.1, 107.9, 89.4, 67.3, 62.4, 62.3, 53.2,
52.1, 44.3, 39.4, 35.9, 29.3, 21.6, 16.9, 16.8
MS (ES): 500.1 [M+Na].sup.+
Example 45
Preparation of intermediate
N-[1-(benzyl)-4-piperidinyl]methyl]-1,4-benzodioxane-5-carboxamide
##STR00072##
A suspension of 1,4-benzodioxan-5-carboxylic acid (1.80 g, 10.0
mmol) and 1,1'-carbonyldiimidazole (1.78 g, 11.0 mmol) in
CH.sub.3CN (100 ml) was stirred at room temperature for 2 h.
1-Benzyl-4-aminomethylpiperidine (from example 37) (2.04 g, 10.0
mmol) in CH.sub.3CN (10 ml) was added to the mixture and stirred
overnight at room temperature. The reaction mixture was
concentrated in vacuo, added EtOAc (200 ml) and washed with
H.sub.2O (3.times.50 ml). The organic layer was dried over
Na.sub.2SO.sub.4 and evaporated in vacuo to a solid material. The
residue was separated with flash chromatography (SiO.sub.2,
EtOAc:MeOH, 1:1) to leave the product as a white solid (2.31 g,
63.1%).
.sup.1H-NMR (200 MHz, CDCl.sub.3): .delta. 7.74 (dd, 1 H), 7.67 (t,
1 H), 7.34-7.15 (m, 5 H), 7.03-6.89 (m, 2 H), 4.43-4.39 (m, 2 H),
4.33-4.29 (m, 2 H), 3.52 (s, 2 H), 3.37 (t, 2 H), 2.93 (d, 2 H),
2.06-1.93 (m, 2 H), 1.77-1.50 (m, 3 H), 1.47-1.28 (m, 2 H)
Example 46
Preparation of intermediate
N-[4-piperidinyl]methyl]-1,4-benzodioxane-5-carboxamide
hydrochloride
##STR00073##
Following the procedure outlined in example 6,
N-[1-(benzyl)-4-piperidinyl]methyl]-1,4-benzodioxane-5-carboxamide
(1.88 g, 5.13 mmol) was converted to the title compound as an white
solid (1.36 g, 85.20%).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.68 (br s, 1 H), 9.37
(br s, 1 H), 7.79 (t, 1 H), 7.71-7.68 (dd, 1 H), 7.03-6.91 (m, 2
H), 4.47-4.45 (m, 2 H), 4.34-4.31 (m, 2 H), 3.52 (d, 2 H), 3.40 (t,
2 H), 2.94-2.82 (q, 2 H), 2.12-1.69 (m, 5 H)
Example 47
Alkylation of
N-[4-piperidinyl]methyl]-1,4-benzodioxane-5-carboxamide
hydrochloride with ethyl 4-bromobutyrate
##STR00074##
Following the procedure outlined in example 7,
N-[4-piperidinyl]methyl]-1,4-benzodioxane-5-carboxamide
hydrochloride (0.56 g, 2.0 mmol) was converted to the title
compound as an oil (0.66 g, 85.3%).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 7.74-7.71 (dd, 1 H),
7.66 (t, 1 H), 7.01-6.90 (m, 2 H), 4.44-4.41 (m, 2 H), 4.33-4.30
(m, 2 H), 4.16-4.09 (q, 2 H), 3.35 (t, 2 H), 2.92 (d, 2 H),
2.38-2.30 (m, 4 H), 2.02-1.50 (m, 7 H), 1.38-1.27 (m, 2 H), 1.25
(t, 3 H)
.sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 173.5, 164.8, 143.4,
141.8, 124.0, 122.2, 121.3, 120.5, 64.9, 63.5, 60.2, 57.9, 53.3,
45.2, 36.0, 32.3, 29.9, 22.2, 14.1
MS (ES): 413.2 [M+Na].sup.+
Example 48
Alkylation of
N-[4-piperidinyl]methyl]-1,4-benzodioxane-5-carboxamide
hydrochloride with diethyl 2-bromoethylphosphonate
##STR00075##
Following the procedure outlined in example 7,
N-[4-piperidinyl]methyl]-1,4-benzodioxane-5-carboxamide
hydrochloride (0.71 g, 2.5 mmol) was converted to the title
compound as an white solid (0.88 g, 80.7%).
.sup.1H-NMR (300 MHz. CDCl.sub.3): .delta. 7.74-7.71 (dd, 1 H),
7.66 (t, 1 H), 6.98-6.93 (m, 2 H), 4.43-4.41 (m, 2 H), 4.33-4.30
(m, 2 H), 4.12-4.05 (m, 6 H), 3.35 (t, 2 H), 2.92 (d, 2 H),
2.58-2.45 (m, 2 H), 2.08-1.90 (m, 4 H), 1.71-1.50 (m, 3 H),
1.36-1.31 (m, 6 H)
.sup.1H-NMR (75 MHz. CDCl.sub.3): .delta. 165.2, 143.9, 142.3,
135.7, 127.6, 124.5, 122.6, 121.7, 121.0, 65.3, 63.9, 62.0, 61.9,
53.3, 52.1, 45.5, 36.3, 30.3, 16.7
MS (ES): 463.2 [M+Na].sup.+
Example 49
Preparation of intermediate
N-[1-(benzyl)-4-piperidinyl]methyl]indole-3-carboxamide
##STR00076##
Following the procedure outlined in example 3, indole-3-carboxylic
acid (5.56 g, 31.0 mmol) was converted to the title compound as an
oil (3.78 g, 35.0%).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.96 (s, 1 H), 7.96 (d,
1 H), 7.67 (s, 1 H), 7.44-7.22 (m, 8 H), 6.24 (t, 1 H), 3.51 (s, 2
H), 3.40 (t, 2 H), 2.92 (d, 2 H), 1.98 (t, 2 H), 1.78-1.67 (m, 3
H), 1.44-1.30 (m, 2 H)
Example 50
Preparation of intermediate
N-[4-piperidinyl]methyl]indole-3-carboxamide
##STR00077##
Following the procedure outlined in example 39,
N-[(1-benzyl-4-piperidinyl)methyl]indole-3-carboxamide (1.50 g, 4.3
mol) was converted to the title compound as a white solid (1.07 g,
96.7%).
.sup.1H-NMR (300 MHz, DMSO-.sub.d6): .delta. 11.56 (br s, 1 H),
8.15-8.12 (m, 1 H), 8.03 (s, 1 H), 7.85 (t, 1 H), 7.41 (d, 1 H),
7.15-7.08 (m, 2 H), 3.12 (t, 2 H), 2.92 (d, 2 H), 2.55-2.49 (m, 1
H), 2.41 (t, 2 H), 1.64-1.60 (m, 3 H), 1.06-1.01 (m, 2 H)
Example 51
Alkylation of N-[4-piperidinyl]methyl]indole-3-carboxamide with
ethyl 4-bromobutyrate
##STR00078##
Following the procedure outlined in example 9,
N-[4-piperidinyl]methyl]indole-3-carboxamide (0.24 g, 0.94 mol) was
converted to the title compound as a white solid (0.16 g,
47.1%).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 9.70 (br s, 1 H),
8.00-7.95 (m, 1 H), 7.78 (s, 1 H), 7.49-7.44 (m, 1 H), 7.30-7.25
(m, 2 H), 6.33 (t, 1 H), 4.20-4.09 (q, 2 H), 3.40 (t, 2 H), 2.97
(d, 2 H), 2.44-2.31 (m, 4 H), 1.99-1.76 (m, 7 H), 1.43-1.24 (m, 5
H)
.sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 173.4, 165.7, 136.4,
128.1, 124.7, 122.7, 121.4, 119.8, 112.1, 60.3, 57.8, 53.2, 44.8,
36.1, 32.2, 29.7, 21.9, 14.2
MS (ES): 394.1 [M+Na].sup.+
Example 52
Alkylation of N-[4-piperidinyl]methyl]indole-3-carboxamide with
2,2,2-trichloroethyl 4-bromobutyrate
##STR00079##
Following the procedure outlined in example 7,
N-[4-piperidinyl]methyl]indole-3-carboxamide (0.94 g, 3.65 mmol)
was converted to the title compound as a white solid (0.84 g,
48.4%).
.sup.1H-NMR (300 MHz, CDCl.sub.3): .delta. 10.08 (br s, 1 H),
7.95-7.92 (m, 1 H), 7.72 (s, 1 H), 7.43 7.40 (m, 1 H), 7.23-7.20
(m, 2 H), 6.31 (t, 1 H), 4.15 (s, 2 H), 3-36 (t, 2 H), 2.90 (d, 2
H), 2.36-2.17 (m, 4 H), 1.89 (t, 2 H), 1.83-1.65 (m, 5 H),
1.36-1.32 (m, 2 H)
.sup.13C-NMR (75 MHz, CDCl.sub.3): .delta. 173.9, 166.0, 136.5,
128.4, 124.6, 122.6, 121.4, 119.6, 112.2, 111.7, 99.7, 57.8, 53.2,
51.5, 44.9, 36.1, 32.0, 30.8, 29.7, 21.9
MS (ES): 497.2 [M+Na].sup.+
Example 53
Hydrolysis of the Trichloroethyl Ester from Example 52
##STR00080##
Following the procedure outlined in example 4, the trichloroethyl
ester from example 52 (0.47 g, 1.0 mmol) was converted to the title
compound as a white solid (0.21 g, 61.1%).
.sup.1H-NMR (300 MHz, DMSO-.sub.d6): 11.63 (s, 1 H), 8.13 (d, 1 H),
8.05 (d, 1 H), 7.97 (t, 1 H), 7.41 (d, 1 H), 7.15-7.05 (m, 2 H),
3.14 (t, 2 H), 3.02 (d, 2 H), 2.50 (t, 2 H), 2.26 (t, 2 H), 2.17
(t, 2 H), 1.75-1.53 (m, 5 H), 1.31-1.21 (m, 2 H)
.sup.13C-NMR (75 MHz, DMSO-d.sub.6): .delta. 174.4, 164.6, 136.0,
127.5, 126.1, 121.6, 120.9, 120.1, 111.7, 110.5, 57.0, 52.2, 43.6,
35.5, 33.4, 28.7, 20.9
MS (ES): 366.2 [M+Na].sup.+
Example 54
Tegaserod
Preparation of the primary amine 2,2,2-trichloroethyl
5-aminopentanoate
A stirred solution of 2,2,2-trichloroethyl 5-bromopentanoate
(prepared by the same method as in example 1) in acetone is added
potassium phtalimide and stirred overnight. The reaction mixture is
filtered and the solvent evaporated in vacuo. The residue is added
EtOAc and washed with H.sub.2O. The organic layer is dried over
Na.sub.2SO.sub.4, filtered and evaporated in vacuo to leave the
title compound. Standard hydrazinolysis in EtOH gives the primary
amine (see scheme 1).
##STR00081## Scheme 1. i, Potassium pthalimide, acetone, ii,
NH.sub.2NH.sub.2, EtOH
Example 55
Tegaserod
Preparation of the monoalkylated amine N-2,2,2-(trichloroethyl
pentanoate)-N'-aminoguanidine
A suspension of thiosemicarbamide is added MeI in EtOH and heated
at 60.degree. C. for 1/2 h and cooled to room temperature. The
resulting suspension is filtered and the filtrate washed with
Et.sub.2O to leave S-methyl isothiosemicarbazide hydroiodide.
S-methyl isothiosemicarbazide hydroiodide is used in the next step
without any further purification. A solution of this compound in
MeOH is added 2,2,2-trichloroethyl 5-aminopentanoate (from example
54) and heated under reflux overnight. The reaction mixture is
cooled to room temperature and the solvent evaporated in vacuo to
leave the title compound. The amine is used in the next step
without any further purification (scheme 2).
##STR00082## Scheme 2. i, MeI, EtOH, ii, 2,2,2-trichloroethyl
5-aminopentanoate, MeOH
Example 56
Tegaserod
Synthesis of the Tegaserod Derivative
To a stirred solution of 5-methoxyindole-3-carboxaldehyde in MeOH
is added N-2,2,2-(trichloroethyl pentanoate)-N'-aminoguanidine at
room temperature. The solution is acidified with conc. aqueous HCl
and stirred overnight. The solvent is evaporated in vacuo and added
MeOH. The solution is added etheral HCl and the precipitate
filtered off. The precipitate is recrystallized from MeOH/Et.sub.2O
to leave the HCl salt of the trichloroethyl ester. This compound is
added to a suspension of Zn and a mixture of 1 M aqueous
KH.sub.2PO.sub.4 and THF and stirred overnight. The suspension is
filtered through a pad of kiselguhr and the solvent evaporated in
vacuo. The residue is separated with flash chromatography to leave
the title compound as a free acid.
##STR00083## Scheme 3. i, N-2,2,2-(trichloroethyl
pentanoate)-N'-aminoguanidine, MeOH/HCl, ii, Zn, 1 M
KH.sub.2PO.sub.4/THF
Example 57
In Vitro Biological Testing of Hydrophilic 5-HT.sub.4 Ligands in
Adenylyl Cyclase Assays
Materials and Methods
Establishment of HEK293 Cell Lines Stably Expressing Human
5-HT.sub.4(b) Receptors
The development of HEK293 cell lines stably expressing human
5-HT.sub.4(b) receptors was described and published previously
(Bach et al. 2001). Briefly, HEK293 cells (ATCC) were grown in
Dulbecco's modified Eagle's medium with 10% fetal calf serum and
penicillin (100 U/ml) and streptomycin (100 .mu.g/ml). Cells were
transfected with plasmid DNA (pcDNA3.1(-) containing human
5-HT.sub.4(b) receptor cDNA) using SuperFect Transfection Reagent
(QIAGEN) according to the manufacturers protocol. Serial dilutions
of transfected cells were plated in 96 well plates containing G418
(geneticin; Amersham) at 0.4 mg/ml, and isolated single colonies of
cells transformed to the neomycin-resistant phenotype were expanded
and tested for expression of serotonin receptors by measuring
serotonin-stimulated adenylyl cyclase activity (Themmen et al.
1993). Transformed cells were always grown in the presence of G418
(0.4 mg/ml). For binding and adenylyl cyclase analysis, stable cell
lines were grown and maintained in UltraCULTURE.TM. general purpose
serum-free medium (BioWhittaker, Walkersville, Md., USA),
supplemented with L-glutamine (2 mM), penicillin (100 U/ml) and
streptomycin (100 .mu.g/ml).
Membrane Preparation for Radioligand Binding and Adenylyl Cyclase
Assay
Membranes were prepared from stably transfected HEK293 cells
cultured on 150-mm cell culture dishes and grown to 80% confluence
in serum-free medium (UltraCULTURE.TM., BioWhittaker) with
penicillin (10 U/ml) and 2 mM L-Glutamine (BioWhittaker). Cells
were washed twice with 10 ml ice-cold HBSS, scraped with a rubber
policeman in 10 ml ice-cold HBSS and collected by centrifugation at
800 g for 5 min at 4.degree. C. The cell pellet was resuspended in
1 ml/dish ice-cold STE buffer (27% (w/v) sucrose, 50 mM Tris-HCl,
pH 7.5 at 20.degree. C., 5 mM EDTA) and homogenized with an
Ultra-Turrax (IKA) homogenizer, using five 10 s bursts with 30 s
cooling in ice-water between bursts. To remove nuclei, the
homogenate was centrifuged at 300 g for 5 min at 4.degree. C. and
the supernatant was further centrifuged at 17000 g for 20 min at
4.degree. C. and the supernatant removed. The crude membrane pellet
was resuspended with ten strokes of tight fitting pestle B in a
Dounce glass-glass homogenizer in 1 ml/dish ice-cold TE (50 mM
Tris-HCl, pH 7.5 at RT, 5 mM EDTA). This procedure was repeated
twice and the resuspended membranes were finally aliquoted and
flash frozen in liquid nitrogen and stored at -70.degree. C. until
use.
Radioligand Binding Assay
Binding assays were performed in 96-well, round-bottom microtiter
plates with total reaction volumes of 50-200 .mu.l, containing the
indicated concentration of [.sup.3H]GR113808 with or without
competing unlabelled ligand in a binding buffer containing 50 mM
Tris-HCl (pH 7.5 at RT), 1 mM EDTA, 5 mM EGTA, 2 mM MgCl.sub.2, 1
mM ascorbate, 0.1% BSA and 100 .mu.M GTP. The plates were incubated
at 23EC for 60 min and harvested onto UniFilter.TM.-96 GF/C.TM.
(Packard Instrument Co., Meriden, Conn., USA), presoaked in 0.3%
polyethyleneimine (Sigma), using a Packard FilterMate Universal
Harvester with 96-well format, and washed 4-6 times with
approximately 0.25 ml/well of ice-cold buffer, containing 50 mM
Tris-HCl (pH 7.0 at RT) and 2 mM MgCl.sub.2. The filters were dried
and counted at approximately 400% efficiency in a Top-Count liquid
scintillation counter (Packard), using 20 .mu.l per filter well of
Micro-Scint liquid scintillation cocktail (Packard).
Adenylyl Cyclase Assay
Adenylyl cyclase activity was measured by determining conversion of
[.alpha.-.sup.32P]ATP to [.sup.32P]cAMP in membranes prepared in
STE by homogenization of cells grown and washed as described above
in a Dounce glass-glass homogenizer by 10 strokes with the
tight-fitting pestle. Membranes were kept on ice prior to assay.
Adenylyl cyclase activities were measured on 10-.mu.l aliquots in a
final volume of 50 .mu.l in the presence of 0.1 mM
[.alpha.-.sup.32P]ATP (1-2.times.10.sup.6 cpm/assay), 4 mM
MgCl.sub.2, 20 .mu.M GTP, 1 mM EDTA, 1 mM [.sup.3H]cAMP (ca. 10,000
cpm/assay), 1 .mu.M 3-isobutyl-1-methyl xanthine (IBMX; Sigma), a
nucleoside triphosphate regenerating system consisting of 20 mM
creatine phosphate (Sigma), 0.2 mg/ml creatine phosphokinase
(Sigma) and 40 U/ml myokinase (Sigma) and additives described in
the text and figures. When forskolin (Calbiochem, La Jolla, Calif.,
USA) was used the concentration was 100 .mu.M. Incubations were for
20 min at 32EC. Cyclic AMP formed was quantified by the double
column chromatography system of Salomon et al. (1974) as modified
by Bockaert et al. (1976).
Analysis of Binding and Adenylyl Cyclase Data
Binding and adenylyl cyclase data were analyzed by non-linear
regression using Microsoft Excel with the Solver add-in, using the
below equations.
Competitive binding assays--The data were fit to the equation
Y=a+(b-a)/(1+x/c) [1] where a is non-specific binding, b is total
binding in the absence of competitor, c is IC.sub.50, and x is the
concentration of competitor. Where relevant, relative binding data
were obtained by recalculating the data using a=0 and b=100.
Activation of adenylyl cyclase--The data were fit to the equation
Y=a+(b-a)x/(c+x) [2] where a is basal adenylyl cyclase activity, b
is maximal adenylyl cyclase activity stimulated by the agonist, c
is EC.sub.50, and x is the concentration of agonist.
IC.sub.50 values from competitive binding assays were converted to
Kb values by the method of Cheng and Prusoff (1973).
Protein Measurements
The protein concentrations in the membrane preparations were
measured with the Micro BCA Protein Assay Reagent Kit (Pierce,
Rockford, Ill., USA) using bovine serum albumin (BSA) as
standard.
Radiochemicals
[.sup.3H]GR113808 (84 Ci/mmol), [.alpha.-.sup.32P]ATP (400 Ci/mmol)
and [.sup.3H]cAMP (30-50 Ci/mmol) were from Amersham
(Buckinghamshire, England).
Compounds
5-Hydroxytryptamine hydrochloride (5-HT, serotonin) was from Sigma
(St. Louis, Mo., USA). GR113808 (1-methyl-1H-indole-3-carboxylic
acid, [1-[2-[(methylsulfonyl)amino]ethyl]-4-piperidinyl]methyl
ester) maleate was from Tocris (Avonmouth, UK). The other compounds
tested were synthesized by Drug Discovery Laboratories AS (DDL)
(Oslo, Norway).
TABLE-US-00001 Standards ##STR00084## DDL-6001 (piboserod)
##STR00085## DDL-6002 Results of in vitro biological testing of new
5-HT.sub.4 ligands in adenylyl cyclase and binding assays,
organised per compound (Table 1) Antagonist pK.sub.b Binding value
Agonist/ affinity (pK.sub.d (individual Antagonist value)
(individual Substance measurements) properties measurements)
GR113808 9.98, 9.87, 9.77, Antagonist 9.94-10.31-10.21- 9.65, 9.82,
9.75 10.71 SB207266 9.88, 9.77 Antagonist 10.76 (piboserod)
DDL-6002 9.89 Antagonist 10.55-10.66 DDL-6003 9.54 Antagonist
9.73-10.36 DDL-6004 9.00 Antagonist 8.76-9.79 DDL-6005 6.56
Antagonist 6.90 DDL-6006 n.d. Unknown 5.71 DDL-6011 6.55 Antagonist
6.42 DDL-6013 8.49 Weak partial 7.78 agonist DDL-6014 9.95 Weak
partial 8.53 agonist DDL-6015 9.17 Antagonist 8.70 DDL-6016 8.55
Weak partial 8.49 agonist DDL-6021 6.24 Partial agonist 7.50
DDL-6022 6.62-8.31 Partial agonist 7.89 DDL-6023 5.49-6.95 Partial
agonist 6.64 DDL-6024 n.d. n.d. 6.35 DDL-6025 n.d. n.d 6.23
DDL-6032 8.36 Partial agonist 8.19 DDL-6040 9.72 Antagonist 10.65
DDL-6041 9.95 Antagonist 10.29 DDL-6042 10.14 Antagonist 10.81
DDL-6043 10.14 Antagonist 10.48 DDL-6044 9.16 Antagonist 9.55
DDL-6045 8.47 Antagonist 8.84 n.d. not determined
* * * * *